Search

Background: Awake mapping has been associated with decreased neurological deficits and increased extent of resection in eloquent glioma resections. However, its effect within clinically relevant glioblastoma subgroups remains poorly understood. We aimed to assess the benefit of this technique in subgroups of patients with glioblastomas based on age, preoperative neurological morbidity, and Karnofsky Performance Score (KPS). Methods: In this propensity score-matched analysis of an international, multicentre, cohort study (GLIOMAP), patients were recruited at four tertiary centres in Europe (Erasmus MC, Rotterdam and Haaglanden MC, The Hague, Netherlands, and UZ Leuven, Leuven, Belgium) and the USA (Brigham and Women's Hospital, Boston, MA). Patients were eligible if they were aged 18–90 years, undergoing resection, had a histopathological diagnosis of primary glioblastoma, their tumour was in an eloquent or near-eloquent location, and they had a unifocal enhancing lesion. Patients either underwent awake mapping during craniotomy, or asleep resection, as per treating physician or multidisciplinary tumour board decision. We used propensity-score matching (1:3) to match patients in the awake group with those in the asleep group to create a matched cohort, and to match patients from subgroups stratified by age (

The value of mapping musical function during awake craniotomy is unclear. Hence, this systematic review was conducted to examine the feasibility and added value of music mapping in patients undergoing awake craniotomy. An extensive search, on 26 March 2021, in four electronic databases (Medline, Embase, Web of Science and Cochrane CENTRAL register of trials), using synonyms of the words "Awake Craniotomy" and "Music Performance," was conducted. Patients performing music while undergoing awake craniotomy were independently included by two reviewers. This search resulted in 10 studies and 14 patients. Intra-operative mapping of musical function was successful in 13 out of 14 patients. Isolated music disruption, defined as disruption during music tasks with intact language/speech and/or motor functions, was identified in two patients in the right superior temporal gyrus, one patient in the right and one patient in the left middle frontal gyrus and one patient in the left medial temporal gyrus. Pre-operative functional MRI confirmed these localizations in three patients. Assessment of post-operative musical function, only conducted in seven patients by means of standardized (57%) and non-standardized (43%) tools, report no loss of musical function. With these results, we conclude that mapping music is feasible during awake craniotomy. Moreover, we identified certain brain regions relevant for music production and detected no decline during follow-up, suggesting an added value of mapping musicality during awake craniotomy. A systematic approach to map musicality should be implemented, to improve current knowledge on the added value of mapping musicality during awake craniotomy.

Three-dimensional (3D) stereophotogrammetry is a novel imaging technique that has gained popularity in the medical field as a reliable, non-invasive, and radiation-free imaging modality. It uses optical sensors to acquire multiple 2D images from different angles which are reconstructed into a 3D digital model of the subject's surface. The technique proved to be especially useful in craniofacial applications, where it serves as a tool to overcome the limitations imposed by conventional imaging modalities and subjective evaluation methods. The capability to acquire high-dimensional data in a quick and safe manner and archive them for retrospective longitudinal analyses, provides the field with a methodology to increase the understanding of the morphological development of the cranium, its growth patterns and the effect of different treatments over time.This review describes the role of 3D stereophotogrammetry in the evaluation of craniosynostosis, including reliability studies, current and potential clinical use cases, and practical challenges. Finally, developments within the research field are analyzed by means of bibliometric networks, depicting prominent research topics, authors, and institutions, to stimulate new ideas and collaborations in the field of craniofacial 3D stereophotogrammetry.We anticipate that utilization of this modality's full potential requires a global effort in terms of collaborations, data sharing, standardization, and harmonization. Such developments can facilitate larger studies and novel deep learning methods that can aid in reaching an objective consensus regarding the most effective treatments for patients with craniosynostosis and other craniofacial anomalies, and to increase our understanding of these complex dysmorphologies and associated phenotypes.

Little is known about the results of young vascular neurosurgeons who perform only microsurgical clip reconstruction in the era since the International Subarachnoid Aneurysm Trial (ISAT) or about the training and caseload required to equivocate the results of senior, more experienced colleagues. The aim of this study was to compare clinical outcomes of patients treated by young and senior vascular neurosurgeons at Erasmus MC University Medical Center Rotterdam, adjusting for case mix.A partially prospective and partially retrospective database was used. Hierarchical mixed models with a random intercept for surgeon were used for confounder adjustment, and propensity score matching for complexity was used to create comparable groups.The study included 609 patients harboring 767 aneurysms. Most (86%) of the aneurysms had at least 1 complexity characteristic, with the majority having 3 characteristics. The most often encountered complexity characteristics were the presence of a broad neck and the presence of branches emerging from the aneurysm. Use of temporary clipping and skull base approaches was significantly higher in the young vascular neurosurgeons group (P0.0001). The complexity score differed significantly between senior and young vascular neurosurgeons (P0.001). After propensity score matching for complexity, multivariable logistic regression showed young vascular neurosurgeons to be significantly associated with better outcomes for ruptured aneurysms (propensity score weighted odds ratio 0.55 [95% confidence interval 0.35-0.88], P = 0.01).In a high-volume neurovascular center where both endovascular and microsurgical treatment options are available, young vascular neurosurgeons can be trained to achieve at least the same results as their senior colleagues despite increased complexity.

Background Evidence-based cognitive rehabilitation programs for brain tumor patients are not widely available, despite the high need. We aimed to evaluate the effects of a tablet-based cognitive rehabilitation program on cognitive performance, cognitive complaints, fatigue, and psychological distress in primary brain tumor patients following neurosurgery. Also, attrition, adherence and patient satisfaction with the program were evaluated. Methods Adults with presumed low-grade glioma and meningioma were recruited before surgery. Three months thereafter, participants were allocated to the intervention group or waiting-list control group using minimization. The 10-week eHealth app ReMind, based on the effective face-to-face intervention, consisted of psychoeducation, strategy-training and attention retraining. Performance-based cognitive outcomes and patient-reported outcomes were assessed before surgery and 3, 6 and 12 months thereafter. Mean scores, percentages of cognitively impaired individuals and reliable change indices (RCIs) were compared between groups. Results Sixty-two out of 183 eligible patients were randomized. Of the people who declined, 56% reported that participation would to be too burdensome. All participants found a tablet-app suitable for delivery of cognitive rehabilitation and 90% rated the program as “good” or “excellent”. Performance-based cognitive outcomes and patient-reported outcomes did not significantly differ in group means over time nor RCIs between the intervention (final n = 20) and control group (final n = 25). Conclusions Recruitment at this early stage was difficult, resulting in limited statistical power. No significant effects were demonstrated, while adherence and satisfaction with the eHealth program were good. In clinical practice, ReMind may be helpful, if timing would be adapted to patients’ needs.

Background The current understanding of mechanisms behind migraine pain has been greatly enhanced with the recent therapies targeting calcitonin gene-related peptide and its receptor. The clinical efficacy of calcitonin gene-related peptide-blocking drugs indicates that, at least in a considerable proportion of patients, calcitonin gene-related peptide is a key molecule in migraine pain. There are several receptors and molecular pathways that can affect the release of and response to calcitonin gene-related peptide. One of these could be purinergic receptors that are involved in nociception, but these are greatly understudied with respect to migraine. Objective We aimed to explore purinergic receptors as potential anti-migraine targets. Methods We used the human middle meningeal artery as a proxy for the trigeminal system to screen for possible anti-migraine candidates. The human findings were followed by intravital microscopy and calcitonin gene-related peptide release measurements in rodents. Results We show that the purinergic P2Y13 receptor fulfills all the features of a potential anti-migraine target. The P2Y13 receptor is expressed in both the human trigeminal ganglion and middle meningeal artery and activation of this receptor causes: a) middle meningeal artery contraction in vitro; b) reduced dural artery dilation following periarterial electrical stimulation in vivo and c) a reduction of CGRP release from both the dura and the trigeminal ganglion in situ. Furthermore, we show that P2X3 receptor activation of the trigeminal ganglion causes calcitonin gene-related peptide release and middle meningeal artery dilation. Conclusion Both an agonist directed at the P2Y13 receptor and an antagonist of the P2X3 receptor seem to be viable potential anti-migraine therapies.

Intracranial pressure (ICP) monitoring is one of the mainstays in the treatment of severe traumatic brain injury (TBI), but different approaches to monitoring exist. The aim of this systematic review and meta-analysis is to compare the effectiveness and complication rate of ventricular drainage (VD) versus intracranial parenchymal (IP) catheters to monitor and treat raised ICP in patients with TBI. Pubmed, Embase, Web of Science, Google Scholar, and the Cochrane Database were searched for articles comparing ICP monitoring-based management with VDs and monitoring with IP monitors through March 2018. Study selection, data extraction, and quality assessment were performed independently by two authors. Outcomes assessed were mortality, functional outcome, need for decompressive craniectomy, length of stay, overall complications, such as infections, and hemorrhage. Pooled effect estimates were calculated with random effects models and expressed as relative risk (RR) for dichotomous outcomes and mean difference (MD) for ordinal outcomes, with corresponding 95% confidence intervals (CI). Six studies were included: one randomized controlled trial and five observational cohort studies. Three studies reported mortality, functional outcome, and the need for a surgical decompression, and three only reported complications. The quality of the studies was rated as poor, with critical or serious risk of bias. The pooled analysis did not show a statistically significant difference in mortality (RR = 0.90, 95% CI = 0.60-1.36, p = 0.41) or functional outcome (MD = 0.23, 95% CI = 0.67-1.13, p = 0.61). The complication rate of VDs was higher (RR = 2.56, 95% CI = 1.17-5.61, p = 0.02), and consisted mainly of infectious complications; that is, meningitis. VDs caused more complications, particularly more infections, but there was no difference in mortality or functional outcome between the two monitoring modalities. However, the studies had a high risk of bias. A need exists for high quality comparisons of VDs versus IP monitor-based management strategies on patient outcomes.

Background The membrane of Liliequist is one of the best-known inner arachnoid membranes and an essential intraoperative landmark when approaching the interpeduncular cistern but also an obstacle in the growth of lesions in the sellar and parasellar regions. The limits and exact anatomical description of this membrane are still unclear, as it blends into surrounding structures and joins other arachnoid membranes. Methods We performed a systematic narrative review by searching for articles describing the anatomy and the relationship of the membrane of Liliequist with surrounding structures in MEDLINE, Embase and Google Scholar. Included articles were cross-checked for missing references. Both preclinical and clinical studies were included, if they detailed the clinical relevance of the membrane of Liliequist. Results Despite a common definition of the localisation of the membrane of Liliequist, important differences exist with respect to its anatomical borders. The membrane appears to be continuous with the pontomesencephalic and pontomedullary membranes, leading to an arachnoid membrane complex around the brainstem. Furthermore, Liliequist’s membrane most likely continues along the oculomotor nerve sheath in the cavernous sinus, blending into and giving rise to the carotid-oculomotor membrane. Conclusion Further standardized anatomical studies are needed to clarify the relation of the membrane of Liliequist with surrounding structures but also the anatomy of the arachnoid membranes in general. Our study supports this endeavour by identifying the knowledge hiatuses and reviewing the current knowledge base.

Background: Surgery of GBM nowadays is usually performed under general anesthesia (GA) and resections are often not as aggressive as possible, due to the chance of seriously damaging the patient with a rather low life expectancy. A surgical technique optimizing resection of the tumor in eloquent areas but preventing neurological deficits is necessary to improve survival and quality of life in these patients. Awake craniotomy (AC) with the use of cortical and subcortical stimulation has been widely implemented for low-grade glioma resections (LGG), but not yet for GBM. AC has shown to increase resection percentage and preserve quality of life in LGG and could thus be of important value in GBM surgery. Methods/design: This study is a prospective, multicenter, randomized controlled trial (RCT). Consecutive patients with a glioblastoma in or near eloquent areas (Sawaya grading II/III) will be 1:1 randomized to awake craniotomy or craniotomy under general anesthesia. 246 patients will be included in neurosurgical centers in the Netherlands and Belgium. Primary end-points are: 1) Postoperative neurological morbidity and 2) Proportion of patients with gross-total resections. Secondary end-points are: 1) Health-related quality of life; 2) Progression-free survival (PFS); 3) Overall survival (OS) and 4) Frequency and severity of Serious Adverse Effects in each group. Also, a cost-benefit analysis will be performed. All patients will receive standard adjuvant treatment with concomitant chemoradiotherapy. Discussion: This RCT should demonstrate whether AC is superior to craniotomy under GA on neurological morbidity, extent of resection and survival for glioblastoma resections in or near eloquent areas. Trial registration: Clinicaltrials.gov: NCT03861299 Netherlands Trial Register (NTR): NL7589

Background: Spinal intradural tumors can be classified as intradural extramedullary or intramedullary tumors. Spinal meningiomas are among the most frequent intradural, extramedullary tumors (IDEMs), representing 12 % of all meningiomas and 25–45 % of all intradural spinal tumors. Objective: To evaluate postoperative outcome, defined by mortality, tumor recurrence and modified Rankin Scale in patients with spinal meningiomas. Furthermore, to identify factors related to these outcome measures and define possible prognosticators. Methods: A large single center retrospective analysis of 166 consecutive spinal meningioma patients during a 29- year period (1989–2018). Results: Female to male ratio was 5.15 to 1. Of all 166 resected tumors, 159 were WHO grade I and seven were WHO grade II. Histopathologically, the psammomatous type was most common (42.8 %). The thoracic region was the most frequent location (71.1 %), followed by cervical and lumbar locations. A complete resection (Simpson I-III) was achieved in 88.7 %. In 12 cases (7.2 %) recurrences of a spinal meningioma occurred after an interval of 0.70–13.78 years. Postoperative complications consisted of CSF leakage and wound healing problems. Three patients died of direct postoperative complications (1.8 %), nine patients died in follow-up due to unrelated causes. Post-operative complications were related to the overall outcome (p = 0.029). Clinical outcome showed improvement in 117 patients out of 148 (79.1 %) according to modified Rankin Scale; 24 patients remained stable and 7 patients deteriorated. Patients with pre-existing bladder/bowel problems and incomplete resections had higher chance of recurrences. Younger patients also had a higher recurrence rate. Follow-up ranged from 0 to 23 years, median of 0.77 years, most were discontinued after 2 years. Conclusions: The primary treatment of spinal meningiomas remains surgery. Complete resection of spinal meningiomas is achieved in most of the cases, however preserving and improving neurological status has priority over complete tumor resection. Morbidity and mortality is relatively low. Longer follow-up periods are recommended, since recurrences can occur after 10–15 years.

_Background_ Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. _Methods_ We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. _Results_ Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm 3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm 3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. _Conclusion_ Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

Objective Glioma patients often complain about problems in daily conversation with a negative impact on quality of life. Disorders in standardized language tests (e.g. naming and fluency), are frequently observed. Most studies claim recovery of language functions within 3 months. However, long-term effects of surgery on spontaneous speech remain unknown. Patients and Methods Eighteen glioma patients were compared to healthy controls in spontaneous speech variables: Type Token Ratio (TTR), Mean Length of Utterance words (MLUw), Incomplete Sentences, Self-corrections and Repetitions. Boston Naming Test (BNT) and Category Fluency (CF) were also assessed. We compared: pre- and 3 months postoperatively (T1-T2), 3 months and 1 year postoperatively (T2-T3), pre- and 1 year postoperatively (T1-T3). Correlations were computed between deviating variables and BNT/CF, tumor localization, and tumor grade. Results Patients had deficits in Incomplete sentences (T1, T2, T3), TTR (T2,T3), MLUw (T3) and Self-corrections (T2). Between T1-T2 no decline was present. Between T2-T3 and T1-T3, there was a decrease of MLUw, Self-corrections and Repetitions and an increase of Incomplete Sentences, BNT and CF were impaired (T1, T2, T3) without differences between test-moments. Most spontaneous speech variables did not correlate with standardized tests. Tumor localization and grade had no influence on spontaneous speech. Conclusion Glioma patients showed impaired spontaneous speech combined with naming and fluency deficits. Surgery appeared to have deteriorated the quality of spontaneous speech until long-term but not the performance at test-level. Hence, spontaneous speech has an added value to standardized tests for diagnosis of language impairments.

Recent publications on the molecular characterization of malignant glioma have had profound impact on the appreciation of tumoral heterogeneity within and between patients. Both these phenomena are implicated in the variability in clinical outcome between patients, as well as the inevitable recurrence of these tumors after conventional treatment. The advent of selective cell culture protocols for the propagation of patient-derived glioma stem-like cells (GSCs) provides researchers the ability to selectively study the cells that could be at the root of tumor proliferation and resistance to therapy. As these techniques are widely applied in contemporary studies and becoming the preferred in vitro model, molecular characterization of GSCs is considered pivotal for the identification and advancement of novel therapies for this devastating disease. This review aims to provide an overview of canonical molecular alterations defining subtypes of malignant glioma as derived from genotypic, transcriptomic and epigenetic profiling in relation to their representation in GSC models. The distribution of these hallmark alterations as found in characterization studies of GSCs is compared between publications. Finally, conclusions of these studies with respect to coverage of driving alterations and translational relevance are provided. By doing so, we provide a contemporary overview of scientific results derived from GSC models and hopefully create appreciation of the advantages and caveats of utilizing these models for studying malignant glioma.

Brain Trauma Foundation (BTF) Guidelines for medical management of severe traumatic brain injury (TBI) have become a global standard for the treatment of TBI patients. We aim to explore the evolution of the guidelines for the management of severe TBI. We reviewed the four editions of the BTF guidelines published over the past 20 years. The 1996 and 2000 editions were merged because of minimal differences, and are referred to as the 1996 edition. We described changes in topics and recommendations over time, and analyzed predictors of survival of recommendations with logistical regression. The guidelines contained 27 recommendations on 18 topics in 2016, 35 recommendations on 15 topics in 2007, and 22 recommendations on 10 topics in 1996. Substantial delays were found between the search for evidence and the guideline publication, ranging from 18 to 34 months. The overall body of evidence comprised 189 studies on 18 topics in 2016, compared with 156 studies on 15 topics in 2007 and 180 studies on 10 topics in 1996. Over time, a total of 175 studies were discarded from the evidence base following more rigorous grading of evidence. A total of 15/23 (65%) of the 1996/2000 recommendations were discarded over time. Out of 12 new recommendations introduced in the 2007 edition, 8 (66%) were discarded in 2016. Survival of recommendations varied between 33% and 100% for level I recommendations and between 11% and 31% for level II and III recommendations. No predictors of survival of recommendations were found. Substantial delays exist between literature search and publication, and survival rate of TBI guideline recommendations is poor. These factors may adversely affect currency and adherence to guidelines. The TBI community should take responsibility for improving the quality of the evidence base and ensuring that the translation of the evidence into guidelines supports clinicians in daily clinical practice.

Within a prospective, observational, multi-center cohort study 68 hospitals (of which 66 responded), mostly academic (n = 60,91%) level I trauma centers (n = 44.67%) in 20 countries were asked to complete questionnaires regarding the "standard of care" for severe neurotrauma patients in their hospitals. From the questionnaire pertaining to ICU management, 12 questions related to admission criteria were selected for this analysis. The questionnaires were completed by 66 centers. The median number of TBI patients admitted to the ICU was 92 [interquartile range (IQR): 52-160] annually. Admission policy varied: in 45 (68%) centers, patients with a Glasgow Come Score (GCS) between 13 and 15 without CT abnormalities but with other risk factors would be admitted to the ICU while the rest indicated that they would not admit these patients routinely to the ICU. We found no association between ICU admission policy and the presence of a dedicated neuro ICU, the discipline in charge of rounds, the presence of step down beds or geographic location (North-Western Europe vs. South-Eastern Europe and Israel). Variation in admission policy, primarily of mild TBI patients to ICU exists, even among high-volume academic centers and seems to be largely independent of other center characteristics. The observed variation suggests a role for comparative effectiveness research to investigate the potential benefit and cost-effectiveness of a liberal versus more restrictive admission policies. (C) 2018 Elsevier Inc. All rights reserved.

There is an ongoing debate on the role of corticosteroids in the treatment of chronic subdural hematoma (CSDH). This study aims to evaluate the effectiveness of corticosteroids for the treatment of CSDH compared to surgery. A systematic search was performed in relevant databases up to January 2019 to identify RCTs or observational studies that compared at least two of three treatment modalities: the use of corticosteroids as a monotherapy (C), corticosteroids as an adjunct to surgery (CS), and surgery alone (S). Outcome measures were good neurological outcome, need for reintervention, mortality, and complications. Effect estimates were pooled and presented as relative risk (RR) with 95% confidence interval (95%CI). Of 796 initially identified studies, 7 were included in the meta-analysis. Risk of bias was generally high. There were no differences in good neurological outcome between treatment modalities. The need for reintervention varied between 4 and 58% in C, 4–12% in CS, and 7–26% in S. The need for reintervention was lower in CS compared with C (RR 3.34 [95% CI 1.53–7.29]; p

INTRODUCTION: Despite hundreds of training models for microsurgery being available in the literature, very few of them are scientifically validated. We chose to validate our low-fidelity training model on flower petals by comparing it head-to-head with a moderate fidelity training model, the anastomosis on chicken leg femoral artery. MATERIALS AND METHODS: A total of 16 participants of different levels of expertise were randomized into 2 groups, 1 training on flower petals and 1 on chicken leg femoral arteries. The groups were evaluated on performing a rat femoral artery anastomosis using the validated Stanford Microsurgical Assessment (SMaRT) Scale. The Mann-Whitney U test was used to check for statistically significant differences between the groups. The flower petal sutures were also evaluated and Pearson correlation was used to check for associations between better petal anastomosis scores and better final SMaRT results. RESULTS: After 6 weeks of flower petal training, microsurgical trainees had significantly better overall SMaRT scores than trainees using chicken leg training, better fine tissue feeling, and better scores in knot tying. The anastomosis times for the rat femoral arteries did not differ between the 2 groups. Good scores for flower petals strongly correlated with a better SMaRT score for the anastomosis. The number of rats used in training reduced after the implementation of this model in continuous training. CONCLUSIONS: The flower petal technique, despite being a low-fidelity model, shows superiority in developing fine tissue feeling and improved knot tying in microsurgery beginners and intermediate level practitioners adding this training model to their program. Further research needs to establish if the improvements also apply to already seasoned microsurgeons and whether the petal score has predictive value for future clinical application.

GABAergic fast-spiking parvalbumin-positive (PV) interneurons are frequently myelinated in the cerebral cortex. However, the factors governing the topography of cortical interneuron myelination remain incompletely understood. Here, we report that segmental myelination along neocortical interneuron axons is strongly predicted by the joint combination of interbranch distance and local axon caliber. Enlargement of PV+ interneurons increased axonal myelination, while reduced cell size led to decreased myelination. Next, we considered regular-spiking SOM+ cells, which normally have relatively shorter interbranch distances and thinner axon diameters than PV+ cells, and are rarely myelinated. Consistent with the importance of axonal morphology for guiding interneuron myelination, enlargement of SOM+ cell size dramatically increased the frequency of myelinated axonal segments. Lastly, we confirm that these findings also extend to human neocortex by quantifying interneuron axonal myelination from ex vivo surgical tissue. Together, these findings establish a predictive model of neocortical GABAergic interneuron myelination determined by local axonal morphology.

Background Migraine is associated with activation of the trigeminovascular system, release of calcitonin gene-related peptide (CGRP) and dilation of dural arteries. Novel treatments target calcitonin gene-related peptide or its receptor, which are present in all vascular beds, raising cardiovascular concerns. Erenumab is a human CGRP-receptor antibody approved for the prophylactic treatment of migraine. Methods We characterised the relaxant responses to CGRP in the absence and presence of erenumab (1 μM) in isolated human middle meningeal, internal mammary and (proximal and distal) coronary arteries. Furthermore, in human internal mammary arteries from cardiovascularly-compromised patients, we assessed the pharmacological specificity of erenumab by investigating whether the vasodilatory responses to acetylcholine, sodium nitroprusside, pituitary adenylate cyclase activating polypeptide-38 (PACAP), vasoactive intestinal peptide and nicardipine, along with the vasoconstrictor responses to dihydroergotamine, were modified by erenumab. Results Calcitonin gene-related peptide induced concentration-dependent vasodilatory responses in all vessels studied that were significantly antagonised by erenumab. In human internal mammary arteries from cardiovascularly-compromised patients, the responses to acetylcholine, sodium nitroprusside, PACAP, vasoactive intestinal peptide, nicardipine and dihydroergotamine were unaffected by erenumab. Conclusion Erenumab inhibits calcitonin gene-related peptide-induced vasodilatory responses in human middle meningeal arteries, human internal mammary arteries and human coronary arteries. Moreover, erenumab shows functional specificity as no interaction was observed with the relaxant responses to several vasodilators, nor the dihydroergotamine-dependent vasoconstrictor responses.

Background Surgery for sagittal synostosis aims at correction of skull shape and restoration of growth potential. Small cranial volume is associated with raised intracranial pressure (ICP). Although many techniques have been described, information on postoperative volume related to early and late remodeling is lacking. Methods Between 2004 and 2008, a total of 95 patients were collected who underwent either early extended strip craniectomy or late total cranial remodeling according to age of presentation. Volume was measured on three-dimensional (3D) photogrammetry. Volume measurements were related to cranial index (CI), head circumference (HCsd), and signs of raised ICP. In a small subset of patients, volume measurements on 3D photogrammetry were assessed for inter- and intrarater reliability and compared to 3D computed tomography (CT). Results Volume was increased in all patients before and after surgery compared to normative values. Postoperatively, late total cranial remodeling resulted in a slightly larger volume than early extended strip craniectomy. Volume measurements showed a good correlation with HCsd (0.67) and a poor relationship with CI (0.13). Headache occurred more frequently in patients with a lower cranial volume. Although papilledema and reoperation showed the same trend, the numbers were too small for statistical analysis. Reproducibility of volume measurements on 3D photogrammetry was high, as was the correlation with measurements on CT. Conclusion Late total cranial remodeling results in a larger postoperative volume, as measured on 3D photogrammetry, than extended strip craniectomy. Clinical signs of raised ICP occur more frequently in patients with a smaller volume. To measure volume, 3D photogrammetry is a good alternative to CT.

Background The prevalence of hypothalamic-pituitary dysfunction after aneurysmal subarachnoid hemorrhage has not been precisely determined, and conflicting results have been reported in the literature. Objective To perform a systematic review and meta-analysis investigating the prevalence of pituitary insufficiency after aneurysmal subarachnoid hemorrhage and to focus on basal serum and dynamic test differences. Methods The prevalence of pituitary dysfunction was quantified at 3 to 6 months and >6 months after aneurysmal subarachnoid hemorrhage. Proportions were transformed with the logit transformation. A subgroup analysis was performed focusing on the differences in outcome between basal serum and dynamic tests for the diagnosis of growth hormone deficiency (GHD) and secondary adrenal insufficiency. Results Overall prevalence of hypopituitarism differed considerably between studies, ranging from 0.05 to 0.45 in studies performed between 3 and 6 months after the event and from 0 to 0.55 in long-term studies (>6 months), with pooled frequencies of 0.31 (95% confidence interval [CI]: 0.22-0.43) and 0.25 (95% CI: 0.16-0.36), respectively. Pooled frequency of GHD at 3 to 6 months was 0.14 (95% CI: 0.08-0.24). At >6 months, GHD prevalence was 0.19 (95% CI: 0.13-0.26) overall, but ranged from 0.15 (95% CI: 0.06-0.33) with the insulin tolerance test to 0.25 (95% CI: 0.15-0.36) using the growth hormone releasing hormone + arginine test. Conclusion Hypopituitarism is a common complication in patients with aneurysmal subarachnoid hemorrhage, with GHD being the most prevalent diagnosis. We showed that variations in prevalence rates in the literature are partly due to methodological differences among pituitary function tests. Abbreviations ACTH, adrenocorticotropic hormoneaSAH, aneurysmal subarachnoid hemorrhageGHD, growth hormone deficiencyGHRH, growth hormone-releasing hormoneGST, glucagon stimulation testIGF, insulin-like growth factor 1ITT, insulin tolerance testSAH, subarachnoid hemorrhage.

BackgroundImmunosuppressive protumoral M2 macrophages are important in pathogenesis, progression, and therapy resistance in glioblastoma (GBM) and provide a target for therapy. Recently oncolytic virotherapy in murine models was shown to change these M2 macrophages toward the pro-inflammatory and antitumoral M1 phenotype. Here we study the effects of the oncolytic virotherapy Delta24-RGD in humans, using both in vitro models and patient material.MethodsHuman monocyte-derived macrophages were co-cultured with Delta24-RGD–infected primary glioma stem-like cells (GSCs) and were analyzed for their immunophenotype, cytokine expression, and secretion profiles. Cerebrospinal fluid (CSF) from 18 Delta24-RGD–treated patients was analyzed for inflammatory cytokine levels, and the effects of these CSF samples on macrophage phenotype in vitro were determined. In addition, tumor macrophages in resected material from a Delta24-RGD–treated GBM patient were compared with 5 control GBM patient samples by flow cytometry.ResultsHuman monocyte-derived M2 macrophages co-cultured with Delta24-RGD–infected GSCs shifted toward an M1-immunophenotype, coinciding with pro-inflammatory gene expression and cytokine production. This phenotypic switch was induced by the concerted effects of a change in tumor-produced soluble factors and the presence of viral particles. CSF samples from Delta24-RGD–treated GBM patients revealed cytokine levels indicative of a pro-inflammatory microenvironment. Furthermore, tumoral macrophages in a Delta24-RGD–treated patient showed significantly greater M1 characteristics than in control GBM tissue.ConclusionTogether these in vitro and patient studies demonstrate that local Delta24-RGD therapy may provide a therapeutic tool to promote a prolonged shift in the protumoral M2 macrophages toward M1 in human GBM, inducing a pro-inflammatory and potentially tumor-detrimental microenvironment.

Purpose DNX-2401 (Delta-24-RGD; tasadenoturev) is a tumor-selective, replication-competent oncolytic adenovirus. Preclinical studies demonstrated antiglioma efficacy, but the effects and mechanisms of action have not been evaluated in patients. Methods A phase I, dose-escalation, biologic-end-point clinical trial of DNX-2401 was conducted in 37 patients with recurrent malignant glioma. Patients received a single intratumoral injection of DNX-2401 into biopsy-confirmed recurrent tumor to evaluate safety and response across eight dose levels (group A). To investigate the mechanism of action, a second group of patients (group B) underwent intratumoral injection through a permanently implanted catheter, followed 14 days later by en bloc resection to acquire post-treatment specimens. Results In group A (n = 25), 20% of patients survived > 3 years from treatment, and three patients had a ≥ 95% reduction in the enhancing tumor (12%), with all three of these dramatic responses resulting in > 3 years of progression-free survival from the time of treatment. Analyses of post-treatment surgical specimens (group B, n = 12) showed that DNX-2401 replicates and spreads within the tumor, documenting direct virus-induced oncolysis in patients. In addition to radiographic signs of inflammation, histopathologic examination of immune markers in post-treatment specimens showed tumor infiltration by CD8+ and T-bet+ cells, and transmembrane immunoglobulin mucin-3 downregulation after treatment. Analyses of patient-derived cell lines for damage-associated molecular patterns revealed induction of immunogenic cell death in tumor cells after DNX-2401 administration. Conclusion Treatment with DNX-2401 resulted in dramatic responses with long-term survival in recurrent high-grade gliomas that are probably due to direct oncolytic effects of the virus followed by elicitation of an immune-mediated antiglioma response.

Objective Neuronavigation systems are routinely used during neurosurgical procedures. Currently, new imaging technologies are emerging, such as virtual, augmented, and mixed reality. With mixed-reality devices, the user can analyze and interact with the real environment using virtual objects. The aim of this prospective pilot study was to offer a proof of concept by testing the clinical feasibility and accuracy of a wearable mixed-reality device (Hololens) for preoperative neurosurgical planning. Methods In patients with an indication for brain tumor surgery, preoperative planning of tumor localization with the Hololens was compared with standard neuronavigation in the operating room. Magnetic resonance imaging−based 3-dimensional holograms of the patient's head and tumor were created and projected on the physical patient's head using the Hololens. The 2-dimensional projection of the tumor borders as perceived by the neurosurgeon on the skin of the patient's head was outlined both with the Hololens and neuronavigation. Accuracy of the Hololens localization was assessed using neuronavigation as the gold standard. Results Twenty-five patients were included in this study. Holograms were successfully created in all cases. In 9 patients tumor localization with the Hololens did not differ from the standard neuronavigation system and the overall median difference was 0.4 cm (interquartile range 0–0.8). Conclusions This prospective clinical study offers a proof of concept of the clinical feasibility of the Hololens for brain tumor surgery planning in the operating room, with quantitative outcome measures. Further development is needed to improve the accuracy of this wearable mixed-reality device.

Background At current prognostication of low grade glioma remains suboptimal and might be improved with additional markers. These may guide treatment decisions, in particular on early adjuvant therapy versus wait and see after surgery. Methods We used a targeted Next-Generation Sequencing panel to assess mutational and copy number status of selected genes and chromosomes in a consecutive series of adult grade II supratentorial glioma, and assessed the impact of molecular markers of interest on overall survival. Results 207 IDH mutated grade II glioma samples were analyzed with a median follow-up of 6.9 years. Loss of region 9p21.3 did not show a correlation with outcome in IDH mutated 1p/19q-codeleted oligodendroglioma or IDH mutated astrocytoma. We found a significant shorter overall survival with univariable analysis in IDH mutated astrocytoma patients with trisomy of chromosome 7 (Log rank P = 0.044) and in IDH mutated 1p/19q-codeleted oligodendroglioma patients with a PTEN mutation (Log rank P = 0.033). We could not validate these findings in multivariate analysis or in the TCGA dataset. Conclusions Loss of 9p21.3 is not associated with outcome in a molecularly defined cohort of grade II glioma and therefore it remains unclear if loss of 9p21.3 can be used as additional marker of anaplasia or to guide treatment decisions. Trisomy of chromosome 7 in IDH mutated astrocytoma and PTEN mutations in IDH mutated oligodendroglioma are potential markers of poor prognosis, but require confirmation in larger series. Electronic supplementary material The online version of this article (10.1007/s11060-018-2867-8) contains supplementary material, which is available to authorized users.

Background Cognitive preservation is crucial in glioma surgery, as it is an important aspect of daily life functioning. Several studies claimed that surgery in eloquent areas is possible without causing severe cognitive damage. However, this conclusion was relatively ungrounded due to the lack of extensive neuropsychological testing in homogenous patient groups. In this study, we aimed to elucidate the short-term and long-term effects of glioma surgery on cognition by identifying all studies who conducted neuropsychological tests preoperatively and postoperatively in glioma patients. Methods We systematically searched the electronical databases Embase, Medline OvidSP, Web of Science, PsychINFO OvidSP, PubMed, Cochrane, Google Scholar, Scirius and Proquest aimed at cognitive performance in glioma patients preoperatively and postoperatively. Results We included 17 studies with tests assessing the cognitive domains: language, memory, attention, executive functions and/or visuospatial abilities. Language was the domain most frequently examined. Immediately postoperatively, all studies except one, found deterioration in one or more cognitive domains. In the longer term (3–6/6–12 months postoperatively), the following tests showed both recovery and deterioration compared with the preoperative level: naming and verbal fluency (language), verbal word learning (memory) and Trailmaking B (executive functions). Conclusions Cognitive recovery to the preoperative level after surgery is possible to a certain extent; however, the results are too arbitrary to draw definite conclusions and not all studies investigated all cognitive domains. More studies with longer postoperative follow-up with tests for cognitive change are necessary for a better understanding of the conclusive effects of glioma surgery on cognition.

Inflammation plays a key role in the pathophysiology of Glioblastoma Multiforme (GBM). Here we focus on the contribution of the so far largely ignored complement system. ELISA and immunohistochemistry were combined to assess levels and localization of critical components of the initiation- and effector pathways of the complement cascade in sera and tumor tissue from GBM patients and matched controls. Serum levels of factor-B were decreased in GBM patients whereas C1q levels were increased. C1q and factor-B deposited in the tumor tissue. Deposition of C3 and C5b-9 suggests local complement activation. MBL deficiency, based on serum levels, was significantly less frequent among GBM patients compared to controls (14% vs. 33%). Therefore low levels of MBL may protect against the initiation/progression of GBM. (C) 2014 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

Oncolytic viruses (OV) have broad potential as an adjuvant for the treatment of solid tumors. The present study addresses the feasibility of clinically applicable drugs to enhance the oncolytic potential of the OV Delta24-RGD in glioblastoma. In total, 446 drugs were screened for their viral sensitizing properties in glioblastoma stem-like cells (GSCs) in vitro. Validation was done for 10 drugs to determine synergy based on the Chou Talalay assay. Mechanistic studies were undertaken to assess viability, replication efficacy, viral infection enhancement and cell death pathway induction in a selected panel of drugs. Four viral sensitizers (fluphenazine, indirubin, lofepramine and ranolazine) were demonstrated to reproducibly synergize with Delta24-RGD in multiple assays. After validation, we underscored general applicability by testing candidate drugs in a broader context of a panel of different GSCs, various solid tumor models and multiple OVs. Overall, this study identified four viral sensitizers, which synergize with Delta24-RGD and two other strains of OVs. The viral sensitizers interact with infection, replication and cell death pathways to enhance efficacy of the OV.

Oncological applications of Raman spectroscopy have been contemplated, pursued, and developed at academic level for at least 25 years. Published studies aim to detect pre-malignant lesions, detect cancer in less invasive stages, reduce the number of unnecessary biopsies and guide surgery towards the complete removal of the tumour with adequate tumour resection margins. This review summarizes actual clinical needs in oncology that can be addressed by spontaneous Raman spectroscopy and it provides an overview over the results that have been published between 2007 and 2017. An analysis is made of the current status of translation of these results into clinical practice. Despite many promising results, most of the applications addressed in scientific studies are still far from clinical adoption and commercialization. The main hurdles are identified, which need to be overcome to ensure that in the near future we will see the first Raman spectroscopy-based solutions being used in routine oncologic diagnostic and surgical procedures.

Early resection is standard of care for presumed low-grade gliomas. This is based on studies including only tumors that were post-surgically confirmed as low-grade glioma. Unfortunately this does not represent the clinicians’ situation wherein he/she has to deal with a lesion on MRI that is suspect for low-grade glioma (i.e. without prior knowledge on the histological diagnosis). We therefore aimed to determine the optimal initial strategy for patients with a lesion suspect for low-grade glioma, but not histologically proven yet. We retrospectively identified 150 patients with a resectable presumed low-grade-glioma and who were otherwise in good clinical condition. In this cohort we compared overall survival between three types of initital treatment strategy: a wait-and-scan approach (n = 38), early resection (n = 83), or biopsy for histopathological verification (n = 29). In multivariate analysis, no difference was observed in overall survival for early resection compared to wait-and-scan: hazard ratio of 0.92 (95% CI 0.43–2.01; p = 0.85). However, biopsy strategy showed a shorter overall survival compared to wait-and-scan: hazard ratio of 2.69 (95% CI 1.19–6.06; p = 0.02). In this cohort we failed to confirm superiority of early resection over a wait-and-scan approach in terms of overall survival, though longer follow-up is required for final conclusion. Biopsy was associated with shorter overall survival.

Background Dihydroergotamine (DHE) and sumatriptan are contraindicated in patients with cardiovascular disease because of their vasoconstricting properties, which have originally been explored in proximal coronary arteries. Our aim was to investigate DHE and sumatriptan in the proximal and distal coronary artery, middle meningeal artery and saphenous vein. Methods Blood vessel segments were mounted in organ baths and concentration response curves for DHE and sumatriptan were constructed. Results In the proximal coronary artery, meningeal artery and saphenous vein, maximal contractions to DHE (proximal: 8 ± 4%; meningeal: 32 ± 7%; saphenous: 52 ± 11%) and sumatriptan (proximal: 17 ± 7%; meningeal: 61 ± 18%, saphenous: 37 ± 8%) were not significantly different. In the distal coronary artery, contractions to DHE (5 ± 2%) were significantly smaller than those to sumatriptan (17 ± 9%). At clinically relevant concentrations, mean contractions to DHE and sumatriptan were below 3% in proximal coronary arteries and below 6% in distal coronary arteries. Contractions in the meningeal artery and saphenous vein were higher (7%–38%). Conclusions Contractions to DHE in distal coronary arteries are smaller than those to sumatriptan, while at clinical concentrations they both induce only slight contractions. In meningeal arteries contractions to DHE and sumatriptan are significantly larger, showing their cranioselectivity. Contractions to DHE in the saphenous vein are higher than those in the arteries, confirming its venous contractile properties.

Background Patients with meningiomas carry an increased risk for postoperative venous thromboembolic complications (VTE) including deep venous thrombosis (DVT) and pulmonary embolism (PE). Objective In the present retrospective study we investigated the incidence of VTE and the risk factors involved, in a large cohort of patients surgically treated for an intracranial meningioma at our institution. Methods During the period from January 1997 to January 2009, 581 consecutive patients underwent craniotomy for intracranial meningioma. All patients received low-molecular weight heparins as thromboembolism prophylaxis. Patient demographics and tumor characteristics were gathered via retrospective chart review. Postoperative VTE and hemorrhages were noted. Backward stepwise logistic regression was used to determine the risk factors. Results 80.6% of meningiomas were WHO grade 1; 15.1% WHO grade 2; 4.3% WHO grade 3. Postoperative VTE were observed in 41 patients (7.2%). Of these, DVT was seen in 20 (3.5%) and PE in 26 patients (4.6%). The thromboembolic complication appeared on average 21.1 ± 29.2 days post surgery. The 90-day mortality rate after VTE was 11.2% (23.1% for PE and 5.0% for DVT). Postoperative hemorrhages requiring surgical treatment were found in 2.9% of patients. Risk factors for VTE were body mass index (p = 0.015) for DVT; weight (p = 0.001) and bedridden postoperatively (p = 0.001) for PE; and weight (p = 0.004) and bedridden postoperatively (p = 0.003) for VTE in general. There was no relation between tumor grade and thromboembolic complications. Conclusion The major risk factors for postoperative VTE found in our single center study are patient weight and a bedridden status postoperatively. Prophylactic intervention for this potentially fatal complication should be evaluated against the relative lower risk of postoperative hemorrhages.

Myelination, the insulating ensheathment of axons by oligodendrocytes, is thought to both optimize signal propagation and provide metabolic support. Despite the well-established physiological importance of myelination to neuronal function, relatively little is known about the myelination of GABAergic interneurons in the cerebral cortex. Here, we report that a large fraction of myelin in mouse cerebral cortex ensheaths GABAergic interneurons, reaching up to 80% in hippocampal subregions. Moreover, we find that a very high proportion of neocortical and hippocampal parvalbumin (PV) interneurons exhibit axonal myelination. Using a combination of intracellular recordings and biocytin labeling of ex vivo human neocortex, we also confirm that axons of fast-spiking PV interneurons are extensively myelinated in the human brain. PV interneuron myelination in both mice and humans exhibits a stereotyped topography with a bias towards proximal axonal segments and relatively short internodes (~27 μm) interspersed with branch points. Interestingly, myelin-deficient Shiverer mice exhibit an increased density and more proximal location of en passant boutons, suggesting that myelination might function in part to regulate synapse formation along PV interneuron axons. Taken together, fast-spiking interneuron myelination is likely to have broad implications for cerebral cortex function in health and disease.

Glial tumors consist of a heterogeneous group of primary CNS neoplasms. While the clinical outcome of these tumors varies substantially between different grades (World Health Organization [WHO] grades I–IV), only grade I tumors can be treated curatively.1 In the last decade, substantial effort has been put into characterizing the pathogenic mechanisms underlying this complex group of glial cell–derived tumors. These efforts have led to the establishment of several molecular subclasses of glioma, which differentiate types of gliomas based on their intrinsic molecular distinctions and similarities, rather than the conventional characteristics used for histology-based grading.2–5 Indeed, gene expression–based clustering of glioma from several grades within the WHO grading system proved more predictive of survival than the histological classification.4, 6 Thus far, however, this gain of insight has not led to improved clinical outcome for patients, since there are no specific treatment strategies designed to target specific subtypes of glioma as of yet. Consequently, the development of preclinical models that accurately reflect the molecular heterogeneity of glioma is imperative for both translationally relevant drug screening programs and the advancement of patient-tailored treatment options. Commercially available cell cultures of glioma have been demonstrated to poorly mimic the molecular aberrations found in patient samples.7,8 Furthermore, the xenograft models derived from these cultures do not sufficiently recapitulate the histological hallmarks of glioma.9 With the advent of the cancer stem cell hypothesis, several groups have implemented serum-free (SF) cell culture regimens, originally developed for neural stem cell propagation, to establish glioma stem-like cell (GSC) cultures from fresh tumor tissue.10,11 By analyzing gene expression profiles of GSCs and serum supplemented (SS) cultures, a distinct separation between the aforementioned and the parental tumors was revealed by unsupervised clustering.7 Several groups have reported GSC cultures to be superior with regard to retaining the original patient gene expression signature and histological phenotype in xenografts.7,11,12 This has led to a wide variety of applications for these cell culture assays, ranging from inquiries into fundamental hypotheses13,14 to preclinical testing of novel agents.15–17 Several contradicting publications have since been published on the optimal cell culture methodology,18,19 mandatory molecular aberrations for successful propagation,20–22 and positive selection for gene expression signatures related to specific molecular subtypes in vitro.14, 23 Most of these previous publications have focused on the characterization of successfully propagated specimens of glioblastoma multiforme (GBM; WHO grade IV) from adults. Reports on the culture success of grade II and grade III gliomas are sparse.20,24 Therefore, we undertook a characterization study of a large cohort (N = 261), which addresses the distribution of glioma from all histological entities for the outcome of GSC culture attempt. Within equal WHO grades, correlations between cell culture outcome and patient overall survival were assessed. Tumor samples of both successful and unsuccessful cultures (n = 46 in total) were also subjected to molecular analysis, and a number of molecular traits that influence cell culture success rate were identified, as well as genes that may play a role in this process. These results emphasize the need for, and provide leads to, the development of improved culture protocols supporting growth of all subtypes of glioma. This is essential for implementation of this model in drug screening programs for personalized treatment strategies.

OBJECTIVE Throughout the last decades, full-endoscopic techniques to treat lumbar disc herniation (LDH) have gained popularity in clinical practice. To date, however, no Class I evidence on the efficacy of percutaneous transforaminal endoscopic discectomy (PTED) has been published, and studies describing its safety and short- and long-term efficacy are scarce. In this study the authors aimed to evaluate the clinical outcomes and safety in patients undergoing PTED for LDH. METHODS Patients who underwent PTED for LDH between January 2009 and December 2012 were prospectively followed. The primary outcomes were the visual analog scale (VAS) score for leg pain and the score on the Quebec Back Pain Disability Scale (QBPDS). Secondary outcomes were the perceived experience with the local anesthesia used and satisfaction with the results after 1 year using Likert-type scales. The pretreatment means were compared with the means obtained 6 and 52 weeks after surgery using paired t-tests. RESULTS A total of 166 patients underwent surgery for a total of 167 LDHs. The mean duration of surgery (± SD) was 51.0 ± 9.0 minutes. The 1-year follow-up rate was 95.2%. The mean reported scores on the VAS and QBPDS were 82.5 ± 17.3 mm and 60.0 ± 18.4 at baseline, respectively. Six weeks after surgery, the scores on the VAS and QBPDS were significantly reduced to 28.8 ± 24.5 mm and 26.7 ± 20.6, respectively (p < 0.001). After 52 weeks of follow-up, the scores were further reduced compared with baseline scores (p < 0.001) to 19.6 ± 23.5 mm on the VAS and 20.2 ± 18.1 on the QBPDS. A total of 4 complications were observed, namely 1 dural tear, 1 deficit of ankle dorsiflexion, and 2 cases of transient paresis in the foot due to the use of local anesthetics. CONCLUSIONS PTED appears to be a safe and effective intervention for LDH and has similar clinical outcomes compared to conventional open microdiscectomy. High-quality randomized controlled trials are required to study the efficacy and cost-effectiveness of PTED.

Purpose To report on a female patient diagnosed with Currarino’s triad in adulthood. Case report This case presents an adult patient with a medical history of a congenital anal atresia, a partial sacral agenesis, and a surgically treated ectopic anus. After a coincidentally observed presacral mass by MRI, due to unexplained constipation later in adulthood, Currarino’s triad was suspected in this patient. This triad consists of anorectal malformation(s), sacrococcygeal defects and a presacral mass of various origin. Further investigation confirmed the mass to be a meningocele, and showed a tethered cord and a syrinx. Conclusions In (young) patients with anorectal malformations, although having no other symptoms, further examination might be required to exclude Currarino’s triad. Importance of early diagnosis and multidisciplinary assessment is recommended to establish adequate treatment if needed.

BACKGROUND Chronic subdural hematoma (CSDH) is commonly seen in neurosurgical practice, and the incidence is increasing. Treatment results are highly variable with respect to recurrences and complications. OBJECTIVE To report our single-center experience with the surgical treatment of CSDH in patients on preoperative corticosteroids and to assess possible predictors of outcome. METHODS The medical reports of 496 consecutive patients with CSDHs treated with burr hole craniostomy were analyzed retrospectively. Patient demographics, medication, hematoma, treatment characteristics, and laboratory values were scored in relation to outcome. Data were analyzed with the χ(2) test, independent t test, and multivariate backward regression. RESULTS Mean age was 71.5 ± 13.3 years (range, 18.6-95.4 years); the male-to-female ratio was 3:1. A decreased Glasgow Coma Scale (GCS) was observed in 63.1%, and GCS motor score on admission was < 6 in 25.2%. Recurrence and mortality rates were 11.9% and 5.3%, respectively. Multivariate analysis showed a longer period of preoperative dexamethasone administration (odds ratio [OR], 0.93 per day; P = .02), GCS motor score within 1 week after surgery of 6 (OR, 0.54; P = .02), postoperative complications (OR, 5.3; P < .001), and a left-sided hematoma (OR, 0.42; P = 0.010) to be significantly related to recurrence risk. CONCLUSION The present data suggest that in surgical treatment of CSDH with burr hole craniostomy, extended preoperative corticosteroid administration is associated with a lower recurrence rate. The use of corticosteroids does not seem to be related to a higher incidence of complications and treatment-related death compared with the current literature.

Objective: We pharmacologically characterized pituitary adenylate cyclase–activating polypeptides (PACAPs), vasoactive intestinal peptide (VIP) and the VPAC1, VPAC2 and PAC1 receptors in human meningeal (for their role in migraine) and coronary (for potential side effects) arteries. Methods: Concentration response curves to PACAP38, PACAP27, VIP and the VPAC1 receptor agonist ([Lys15,Arg16,Leu27]-VIP[1-7]-GRF[8-27]) were constructed in the absence or presence of the PAC1 receptor antagonist PACAP6-38 or the VPAC1 receptor antagonist, PG97269. mRNA expression was measured using qPCR. Results: PACAP38 was less potent than VIP in both arteries. Both peptides had lower potency and efficacy in meningeal than in coronary arteries, while mRNA expression of VPAC1 receptor was more pronounced in meningeal arteries. PACAP6-38 reduced the Emax of PACAP27, while PG97269 right-shifted the VIP-induced relaxation curve only in the coronary arteries. Conclusion: The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.

Background: Conditionally-replicating adenoviruses (CRAds) infect and replicate in tumor cells, releasing viral progeny upon lysis of the cell. This is a dynamic and inherently exponential process and, thus, the assessment of CRAds should incorporate these dynamics. In vitro experiments are therefore prone to subjective assessment because no validated assay exists that truly appreciates the dynamics of the process. An objective assay could simplify experiments and reduce the number of CRAd variants required to enter a full preclinical evaluation. Methods: We developed a simple and practical mathematical model incorporating easily obtainable parameters of the interaction between replicating viruses and growing tumor cells in vitro and, in the present study, validate this model by fitting the predicted values to experimentally-derived values. Results: From the exponential curves of cellular growth and the viral propagation rate in glioma cells, we derive the four parameters needed in this model and show a robust fit to experimental data. Because the initial infection conditions appear to significantly influence the final outcome of CRAd experiments, these conditions are determined using the same cells and correlated with the expression of the primary adenovirus receptor CAR (coxsackie and adenovirus receptor). Conclusions: The results obtained shed light upon the method of action of CRAds and provide an objective and practical model and assay for determining and predicting CRAd activity in tumor cells. Copyright © 2010 John Wiley & Sons, Ltd.

The field of gene therapy for malignant glioma has made important advances since the first gene transfer studies were performed 20 years ago. Multiple Phase I/II trials and two Phase III trials have been performed and have demonstrated the feasibility and safety of intratumoral vector delivery in the brain. Sitimagene ceradenovec is an adenoviral vector encoding the herpes simplex thymidine kinase gene, developed by Ark Therapeutics Group plc (UK and Finland) for the treatment of patients with operable high-grade glioma. In preclinical and Phase I/II clinical studies, sitimagene ceradenovec exhibited a significant increase in survival. Although the preliminary results of a Phase III clinical study demonstrated a significant positive effect of sitimagene ceradenovec treatment on time to reintervention or death when compared with standard care treatment (hazard ratio: 1.43; 95% CI: 1.06–1.93; p < 0.05), the European Committee for Medicinal Products for Human Use did not consider the data to provide sufficient evidence of clinical benefit. Further clinical evaluation, powered to demonstrate a benefit on a robust end point, is required. This article focuses on sitimagene ceradenovec and provides an overview of the developments in the field of gene therapy for malignant glioma.

BACKGROUND: Information on the neurocognitive outcome following treatment of benign meningiomas is virtually lacking. This is remarkable considering these patientsś survival is the most favorable of all intracranial tumors. The aim of the present study is therefore to document the extent and nature of neurocognitive deficits in WHO grade I meningioma patients after treatment. METHODS: Eighty-nine WHO grade I meningioma patients who underwent surgery with or without adjuvant radiotherapy were individually matched to 89 healthy controls for age, sex, and educational level. Neurocognitive functioning of patients was assessed at least one year following treatment and compared to that of healthy controls using Student's t-tests. Additionally, associations between tumor characteristics (size, lateralization and localization), treatment characteristics (radiotherapy), and epilepsy burden (based on seizure frequency and antiepileptic drug use) and neurocognitive functioning were investigated. RESULTS: Compared to healthy controls meningioma patients showed significant impairments in executive functioning (p < 0.001), verbal memory (p < 0.001), information processing capacity (p = 0.001), psychomotor speed (p = 0.001), and working memory (p = 0.006). Patients with skull base meningiomas performed significantly lower on three out of six neurocognitive domains when compared to convexity meningiomas. Left-sided as opposed to right sided meningiomas were related to verbal memory deficits. A higher epilepsy burden was significantly associated with lower executive functioning, which primarily could be attributed to antiepileptic drug use. No significant associations were established between neurocognitive status and radiotherapy or tumor volume. CONCLUSIONS: Meningioma patients are characterized by long-term deficits in neurocognitive functioning that can partly be attributed to the use of antiepileptic drugs and tumor location, but not to the use of radiotherapy

Glioblastoma multiforme (GBM), the most frequent malignant brain tumor, has a poor prognosis, but is relatively sensitive to radiation. Both gemcitabine and its metabolite difluorodeoxyuridine (dFdU) are potent radiosensitizers. The aim of this phase 0 study was to investigate whether gemcitabine passes the blood-tumor barrier, and is phosphorylated in the tumor by deoxycytidine kinase (dCK) to gemcitabine nucleotides in order to enable radiosensitization, and whether it is deaminated by deoxycytidine deaminase (dCDA) to dFdU. Gemcitabine was administered at 500 or 1000 mg/m(2) just before surgery to 10 GBM patients, who were biopsied after 1-4 h. Plasma gemcitabine and dFdU levels varied between 0.9 and 9.2 microM and 24.9 and 72.6 microM, respectively. Tumor gemcitabine and dFdU levels varied from 60 to 3580 pmol/g tissue and from 29 to 72 nmol/g tissue, respectively. The gene expression of dCK (beta-actin ratio) varied between 0.44 and 2.56. The dCK and dCDA activities varied from 1.06 to 2.32 nmol/h/mg protein and from 1.51 to 5.50 nmol/h/mg protein, respectively. These enzyme levels were sufficient to enable gemcitabine phosphorylation, leading to 130-3083 pmol gemcitabine nucleotides/g tissue. These data demonstrate for the first time that gemcitabine passes the blood-tumor barrier in GBM patients. In tumor samples, both gemcitabine and dFdU concentrations are high enough to enable radiosensitization, which warrants clinical studies using gemcitabine in combination with radiation.

Background The purpose of the study was to evaluate the effects, frequency, and complications of repeated surgical resection for GBM relapse. Methods A group of 32 patients with tumor recurrence, derived from a total of 126 consecutive patients with prior GBM, treated between 1999 and 2005 in the VU University Medical Center, Amsterdam, Netherlands, were retrospectively studied. Survival, functional status, morbidity, and mortality after starting salvage therapy for recurrent GBM were studied. Survival was analyzed using Kaplan-Meier survival curves, and log-rank statistics were used for group comparison. Results Of the 32 patients with recurrent primary GBM, 20 received repeated surgery as salvage therapy. In 11 (55%) cases, repeated surgery was followed by CT or SRS. Nine (45%) patients receiving only repeated surgery showed significantly lower survival rates compared with the aforementioned 11 cases. The remaining 12 patients received only salvage CT or SRS and showed a significantly prolonged survival compared with the 9 cases receiving repeated surgery only. Surgical morbidity was 15%, and surgical mortality, 5%. Conclusion Despite inherent selection bias, this retrospective analysis suggests that repeated surgery for GBM relapse should only be considered in patients with severe symptoms and if additional salvage treatment can be administered postoperatively.

Purpose: The integrin-targeted conditionally replicating adenovirus Ad5-Δ24RGD has been shown to possess strong oncolytic activity in experimental tumors and is currently being developed toward phase I clinical evaluation for ovarian cancer and malignant glioma. Previously, we reported that combination therapy of Ad5-Δ24RGD with irradiation led to synergistic antitumor activity in s.c. glioma xenografts. In the current study, the underlying mechanism of action to this synergy was studied and the effects of combined therapy were assessed in an orthotopic glioma model. Experimental Design and Results: Sequencing studies in U-87 monolayers showed that delivery of irradiation before Ad5-Δ24RGD infection led to a greater oncolytic effect than simultaneous delivery or infection before irradiation. This effect was not due to enhanced virus production or release. Experiments using a luciferase-encoding vector revealed a small increase in transgene expression in irradiated cells. In tumor spheroids, combination therapy was more effective than Ad5-Δ24RGD or irradiation alone. Staining of spheroid sections showed improved penetration of virus to the core of irradiated spheroids. Mice bearing intracranial tumors received a combination of Ad5-Δ24RGD with 1 × 5 Gy total body irradiation or with 2 × 6 Gy whole brain irradiation. In contrast to the in vitro data and reported results in s.c. tumors, addition of radiotherapy did not significantly enhance the antitumor effect of Ad5-Δ24RGD. Conclusions: Combined treatment with Ad5-Δ24RGD and irradiation shows enhanced antitumor activity in vitro and in s.c. tumors, but not in an orthotopic glioma model. These differential results underscore the significance of the selected tumor model in assessing the effects of combination therapies with oncolytic adenoviruses.

BACKGROUND: The conditionally replicating adenovirus (CRAd) AdDelta24-p53 replicates selectively in Rb mutant cells, and encodes the p53 suppressor protein. It has shown improved oncolytic potency compared to the parental control AdDelta24. As exogenous p53 has been shown to enhance radiosensitivity, the combination of AdDelta24-p53 and AdDelta24 with radiotherapy was assessed in vitro and in vivo against the therapy resistant gliomas.METHODS: In glioma cells, multicellular spheroids and animal xenografts the efficacy of combination therapy was assessed. P53 phosphorylation, induction of apoptosis and viral replication were determined following single or combination therapies.RESULTS: In vitro, AdDelta24-p53 was more effective against glioma cells than the control AdDelta24. Addition of irradiation equally increased the efficacy of both AdDelta24-p53 and AdDelta24 resulting in improved oncolysis compared to single agent treatment. Radiotherapy did not significantly change the replication kinetics of AdDelta24-p53 or AdDelta24. No detectable increase in p53 phosphorylation was observed but combination of radiotherapy and AdDelta24-p53 caused an increase in the percentage of apoptotic cells. In vivo, combination therapy with either AdDelta24 or AdDelta24-p53 significantly increased the number of mice demonstrating tumor regression (100%) as well as long-term survival (50%). No differences between viruses were noted.CONCLUSIONS: Exogenous p53 expression does not appear to increase the synergistic interaction of CRAds combined with radiotherapy. These results however do indicate that radiotherapy provides the time frame in which AdDelta24 and AdDelta24-p53 can eradicate established tumors that would otherwise escape treatment, and establishes the need to combine these modalities to form an effective anti-cancer treatment.

Background In a phase 1 trial conducted at our institute, convection-enhanced delivery (CED) was used to administrate the Delta-24-RGD adenovirus in patients with a recurrent glioblastoma multiforme. Infusion of the virus was preceded by a gadolinium-conjugated diethylenetriamine penta-acetic acid (Gd-DTPA) test-infusion. In the present study, we analyzed the results of Gd-DTPA test infusion through 50 catheters. Methods Thirteen adults with a recurrent glioblastoma multiforme were enrolled in a larger phase 1 multicenter, dose-finding study, in which a conditionally replication-competent adenovirus was administered by CED. Up to 4 infusion catheters per patient were placed intra- and/or peritumorally. Before infusion of the virus, a Gd-DTPA infusion was performed for 6 hours, directly followed by a MRI scan. The MRIs were evaluated for catheter position, Gd-DTPA distribution outcome, and contrast leakage. Results Leakage of Gd-DTPA into the cerebrospinal fluid was detected in 17 of the 50 catheters (34%). Sulcus crossing was the most frequent cause of leakage. In 8 cases, leakage could only be detected on the fluid-attenuated inversion recovery sequence. Nonleaking catheters showed a significantly larger Gd-DTPA distribution fraction (volume of distribution/volume of infusion) than leaking catheters ( P = 0.009). A significantly lower volume of distribution/volume of infusion was observed in intratumoral catheters, compared with peritumoral catheters ( P = 0.004). Gd-DTPA test infusion did not result in significant changes in Karnofsky Performance Score and Neurological Status. Conclusions Pre-CED treatment infusion of Gd-DTPA is an adequate and safe method to identify dysfunctional catheters. The use of an optimized drug delivery catheter is necessary to reduce leakage and improve the efficacy of intracerebral drug infusion.

The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.

Objective Hemodynamic stress, conditioned by the geometry and morphology of the vessel trees, plays an important role in the formation of intracranial aneurysms. The aim of this study was to identify image-based location-specific morphologic parameters that are associated with posterior communicating artery (PCoA) aneurysms. Methods Morphologic parameters obtained from computed tomography angiography of 56 patients with PCoA aneurysms and 23 control patients were evaluated with 3D Slicer, an open-source image analysis software, to generate 3-dimensional models of the aneurysms and surrounding vasculature. Segment lengths, diameters, and vessel-to-vessel angles were examined. To control for genetic and clinical risk factors, the unaffected contralateral side of patients with unilateral PCoA aneurysms was used as a control group for internal carotid artery (ICA)–related parameters. A separate control group with visible PCoAs and aneurysms elsewhere was used as a control group for PCoA-related parameters. Results Internal carotid artery–related parameters were not statistically different between the PCoA aneurysm and control groups. Univariate and multivariate subgroup analysis for patients with visualized PCoAs demonstrated that a larger PCoA diameter was significantly associated with the presence of a PCoA aneurysm (odds ratio = 12.1, 95% confidence interval = 1.3–17.1, P = 0.04) after adjusting for other morphologic parameters. Conclusions Larger PCoA diameters are associated with the presence of PCoA aneurysms. These parameters may provide objective metrics to assess aneurysm formation and growth risk stratification in high-risk patients.

Background: The current standard of care for Glioblastoma Multiforme (GBM) consists of fractionated focal irradiation with concomitant temozolomide (TMZ) chemotherapy. A promising strategy to increase the efficacy of TMZ is through interference with the DNA damage repair machinery, by poly(ADP-ribose) polymerase protein inhibition(PARPi). The objective of the present study was to investigate the therapeutic benefit of combination therapy in patient-derived glioma stem-like cells (GSC). Methods: Combination therapy feasibility was tested on established GBM cell lines U373 and T98. We developed an in vitro drug-screening assay based on GSC cultures derived from a panel of primary patient tissue samples (n = 20) to evaluate the effect of PARPi (ABT-888) monotherapy and combination therapy with TMZ. Therapeutic effect was assessed by viability, double stranded breaks, apoptosis and autophagy assays and longitudinal microscopic cell monitoring was performed. O-6-methylguanine-DNA methyltransferase (MGMT) status was determined by methylation assay and protein expression by western blots. Results: PARPi monotherapy was found to decrease viability by more than 25% in 4 of the 20 GSCs (20%) at 10 mu M. TMZ monotherapy at 50 mu M and 100 mu M was effective in 12 and 14 of the 20 GSCs, respectively. TMZ resistance to 100 mu M was found in 7 of 8 MGMT protein positive cultures. Potentiation of TMZ therapy through PARPi was found in 90% (n = 20) of GSCs, of which 6 were initially resistant and 7 were sensitive to TMZ monotherapy. Increased induction of double stranded breaks and apoptosis were noted in responsive GSCs. There was a trend noted, albeit statistically insignificant, of increased autophagy both in western blots and accumulation of autophagosomes. Conclusion: PARPi mediated potentiation of TMZ is independent of TMZ sensitivity and can override MGMT(-) mediated resistance when administered simultaneously. Response to combination therapy was associated with increased double strand breaks induction, and coincided by increased apoptosis and autophagy. PARPi addition potentiates TMZ treatment in primary GSCs. PARPi could potentially enhance the therapeutic efficacy of the standard of care in GBM.