PLOD2 Is a Prognostic Marker in Glioblastoma That Modulates the Immune Microenvironment and Tumor Progression.

This study aimed to investigate the role of Procollagen-Lysine, 2-Oxoglutarate 5-Dioxygenase 2 (PLOD2) in glioblastoma (GBM) pathophysiology. To this end, PLOD2 protein expression was assessed by immunohistochemistry in two independent cohorts of patients with primary GBM (n1 = 204 and n2 = 203, respectively). Association with the outcome was tested by Kaplan−Meier, log-rank and multivariate Cox regression analysis in patients with confirmed IDH wild-type status. The biological effects and downstream mechanisms of PLOD2 were assessed in stable PLOD2 knock-down GBM cell lines. High levels of PLOD2 significantly associated with (p1 = 0.020; p2< 0.001; log-rank) and predicted (cohort 1: HR = 1.401, CI [95%] = 1.009−1.946, p1 = 0.044; cohort 2: HR = 1.493; CI [95%] = 1.042−2.140, p2 = 0.029; Cox regression) the poor overall survival of GBM patients. PLOD2 knock-down inhibited tumor proliferation, invasion and anchorage-independent growth. MT1-MMP, CD44, CD99, Catenin D1 and MMP2 were downstream of PLOD2 in GBM cells. GBM cells produced soluble factors via PLOD2, which subsequently induced neutrophils to acquire a pro-tumor phenotype characterized by prolonged survival and the release of MMP9. Importantly, GBM patients with synchronous high levels of PLOD2 and neutrophil infiltration had significantly worse overall survival (p < 0.001; log-rank) compared to the other groups of GBM patients. These findings indicate that PLOD2 promotes GBM progression and might be a useful therapeutic target in this type of cancer.

Associated Aneurysms in Infratentorial Arteriovenous Malformations: Role of Aneurysm Size and Comparison with Supratentorial Lesions.

BACKGROUND: The natural history and treatment of brain arteriovenous malformations (AVMs) is the object of ongoing debates and discussions. To capture the entirety of these complex lesions, associated vascular pathologies, such as associated aneurysms (AAs), have to be implemented in future risk stratification models, as they are believed to represent additional risk factors for intracranial hemorrhage. The present study aims to determine AA characteristics in posterior fossa AVMs and to compare with AAs accompanying supratentorial AVMs, with special focus on aneurysm size. METHODS: Patients with cerebral AVMs, treated in our department between 1990 and 2013, were analyzed retrospectively. Only patients with flow-related AAs of the feeding arteries were evaluated. Thus, patients harboring intranidal, venous or remote aneurysms were excluded. RESULTS: Of 485 patients with cerebral AVM, 76 patients harbored an AVM of the posterior fossa. Among those, 22 individuals exhibited a total of 35 AAs (n = 8 patients with multiple AAs). Most common location of AAs was the posterior inferior cerebellar artery (n = 20, 57%) and mean AA diameter was 7.9 mm (SD 5.5). In the subgroup of patients with a single AA, mean aneurysm size in posterior fossa AVMs was with 7.8 mm (SD 6.0; range 2-25 mm) significantly larger than the mean size of AAs with supratentorial AVMs (4.8 mm, SD 3.0; range 2-20 mm; p = 0.048). Intracranial hemorrhage was found in 18 of 22 patients (82%) with infratentorial AVMs, and of these, 11 patients suffered from aneurysm rupture. In 14 patients bearing a single AA, 8 (57%) had sustained hemorrhage from aneurysm rupture. The mean diameter of AAs was as supposed in the ruptured group with 9.8 mm (SD 6.9; range 4-25 mm) significantly larger than in the unruptured AA group exhibiting a mean of 5.0 mm (SD 3.3; range 2-10 mm; p = 0.038). Patients with posterior fossa AVMs and AAs were significantly older as compared to those patients with supratentorial lesions (57.1, SD 12.6 vs. 45.8 years, SD 15.9 years; p = 0.004), which was also evident in the subgroup of patients with single AAs (55.2, SD 11.7 vs. 45.8 years, SD 14.9 years; p = 0.038). CONCLUSIONS: AAs of posterior fossa AVMs are larger in diameter than aneurysms accompanying supratentorial AVMs. AA size influences risk for hemorrhage, which, together with the high number of hemorrhagic events in posterior fossa AVMs, justifies treating these pathologies. The higher age of patients with AVMs of the posterior fossa might be one reason for larger AAs in this cohort, when compared to patients with supratentorial AVMs and AAs.

A retrospective and consecutive analysis of the epidemiology and management of spinal cavernomas over the last 20 years in a single center.

Spinal cavernous malformations (SCM) are rare lesions often presenting with acute onset of symptoms and progressive neurological deterioration due to hemorrhage into the spinal cord. With the aid of modern techniques, their surgical removal became much safer. The present study was undertaken to analyze the outcome of our series of surgically and conservatively treated patients with SCM. Over a period of 20 years, 20 surgically treated and 5 conservatively managed patients with spinal cavernous malformations were identified and enrolled into this analysis. Demographic data, clinical symptoms, localization and extension of the cavernoma, as well as pre- and postoperative neurological status were obtained. The clinical status was assessed using the Frankel score. Patients were followed up clinically and by MRI. Before surgery, 90% (18/20) of our surgical patients were classified as Frankel D (93.8%), whereas two patients (10%) were graded C. None of the patients had a worse Frankel score at the time of discharge. Eighty percent of them (16 cases) remained unchanged, and 20% (4 patients) improved during the first follow-up (mean 6.3 months, range 2-17 months). All improved patients had a superficially located SCM and were operated early (≤3 months). No worsening was observed during extended follow-up (range 9-134 months, mean 44.7 months). Five nonsurgically treated patients showed no significant clinical deterioration over a period of 6.7 years (mean, range 2.9-8 years). SCM localization and number of involved segments had no influence on outcome. Our data show that SCM can be resected with favorable neurological outcome by using intraoperative neuromonitoring. Within the follow-up period, patients treated conservatively remained in a stable neurological condition.

Single center experience with treatment of spinal dural arteriovenous fistulas.

Spinal dural arteriovenous fistulas (SDAVFs) are rare pathologies with a yearly incidence of 5-10 new cases/million, constituting 60-80 % of spinal arteriovenous malformations. Clinical symptoms include progressive paraparesis, paresthesias, bladder, and bowel disturbances. The pathophysiology of SDAVFs is not well elucidated. Microneurosurgery and endovascular techniques are established treatment modalities for permanent fistula occlusion, which are oftentimes accompanied by an amelioration of neurological deficits in the long run. Here, we report our interdisciplinary neurosurgical/neuroradiological management strategy of SDAVFs in 32 patients who were evaluated retrospectively. We focused on clinical presentation, microneurosurgical and interventional technique, early, and late neurological results. Quality of life (QoL) was additionally assessed in 12 patients at last follow-up. We discuss the results against the background of the current literature. Our series and the literature indicate that clinical outcome after treatment of SDAVF is favorable in general. Both neurosurgical and neurointerventional therapies appear to be safe and effective, but short-term neurological deterioration after the intervention constitutes an as-of-yet unsolved problem. Beyond age and preoperative neurological state, presence of comorbidities had a significant influence on neurological outcome in our study sample. Self-assessed physical and mental QoL at long-term follow-up was reduced in quite a number of patients and was associated with a poorer neurological result as well as presence of comorbidities. The patients' perspective in terms of QoL was first investigated in this study, but further research on QoL and psychosocial impairment of SDAVF patients is needed to enable individualized counseling and rehabilitation strategies.

Is an Elevated Preoperative CRP Level a Predictive Factor for Wound Healing Disorders following Lumbar Spine Surgery?

Postoperative wound infections are a prevalent concern among the hospital-associated infections in Europe, leading to prolonged hospital stays, increased morbidity and mortality, and substantial patient burdens. Addressing the root causes of this complication is crucial, especially given the rising number of spine surgeries due to aging populations. METHODS: A retrospective analysis was conducted on a cohort of 3019 patients who underwent lumbar spine surgery over a decade in our department. The study aimed to assess the predictors of wound healing disorders, focusing on laboratory values, particularly inflammatory parameters. RESULTS: Of the 3019 patients, 2.5% (N = 74) experienced deep or superficial wound healing disorders, showing the significant correlation between C-reactive protein (CRP) levels and these disorders (p = 0.004). A multivariate analysis identified several factors, including age, sex, hypertension, diabetes, cardiac comorbidity, surgical duration, dural injury, and blood loss, as being correlated with wound healing disorders. CONCLUSION: Demographic factors, pre-existing conditions, and perioperative variables play a role in the occurrence of adverse effects related to wound healing disorders. Elevated CRP levels serve as an indicator of increased infection risk, though they are not a definitive diagnostic tool for wound healing disorders.

The Roles of AGTRAP, ALKBH3, DIVERSIN, NEDD8 and RRM1 in Glioblastoma Pathophysiology and Prognosis.

This study determined the expression of five novel biomarker candidates in IDH wild-type glioblastoma (GBM) tissues compared to non-malign brain parenchyma, as well as their prognostic relevance for the GBM patients' outcomes. The markers were analysed by immunohistochemistry in tumour tissues (n = 186) and healthy brain tissues (n = 54). The association with the patients' overall survival (OS) and progression-free survival (PFS) was assessed by Kaplan-Meier and log-rank test. The prognostic value of the markers was determined using multivariate Cox proportional hazard models. AGTRAP, DIVERSIN, cytoplasmic NEDD8 (NEDD8c) and RRM1 were significantly overexpressed in tumour tissues compared to the healthy brain, while the opposite was observed for ALKBH3. AGTRAP, ALKBH3, NEDD8c and RRM1 were significantly associated with OS in univariate analysis. AGTRAP and RRM1 were also independent prognostic factors for OS in multivariate analysis. For PFS, only AGTRAP and NEDD8c reached significance in univariate analysis. Additionally, AGTRAP was an independent prognostic factor for PFS in multivariate models. Finally, combined analysis of the markers enhanced their prognostic accuracy. The combination AGTRAP/ALKBH3 had the strongest prognostic value for the OS of GBM patients. These findings contribute to a better understanding of the GBM pathophysiology and may help identify novel therapeutic targets in this type of cancer.

Loss of CCM3 impairs DLL4-Notch signalling: implication in endothelial angiogenesis and in inherited cerebral cavernous malformations.

CCM3, a product of the cerebral cavernous malformation 3 or programmed cell death 10 gene (CCM3/PDCD10), is broadly expressed throughout development in both vertebrates and invertebrates. Increasing evidence indicates a crucial role of CCM3 in vascular development and in regulation of angiogenesis and apoptosis. Furthermore, loss of CCM3 causes inherited (familial) cerebral cavernous malformation (CCM), a common brain vascular anomaly involving aberrant angiogenesis. This study focused on signalling pathways underlying the angiogenic functions of CCM3. Silencing CCM3 by siRNA stimulated endothelial proliferation, migration and sprouting accompanied by significant downregulation of the core components of Notch signalling including DLL4, Notch4, HEY2 and HES1 and by activation of VEGF and Erk pathways. Treatment with recombinant DLL4 (rhDLL4) restored DLL4 expression and reversed CCM3-silence-mediated impairment of Notch signalling and reduced the ratio of VEGF-R2 to VEGF-R1 expression. Importantly, restoration of DLL4-Notch signalling entirely rescued the hyper-angiogenic phenotype induced by CCM3 silence. A concomitant loss of CCM3 and the core components of DLL4-Notch signalling were also demonstrated in CCM3-deficient endothelial cells derived from human CCM lesions (CCMEC) and in a CCM3 germline mutation carrier. This study defined DLL4 as a key downstream target of CCM3 in endothelial cells. CCM3/DLL4-Notch pathway serves as an important signalling for endothelial angiogenesis and is potentially implicated in the pathomechanism of human CCMs.

Intramedullary spinal cord astrocytomas: the influence of localization and tumor extension on resectability and functional outcome.

BACKGROUND: Intramedullary spinal cord tumors (IMSCT) are rare lesions, ependymomas and astrocytomas being the most common ones. Different studies have been published showing results of different treatment strategies as extensive/ limited surgery, biopsy and adjuvant radiation therapy with regard to functional outcome and survival. The present study was undertaken to analyse our series of surgically treated intramedullary astrocytomas in order to identify factors with impact on functional outcome and resectability. METHODS: Over a period of 20 years, among 215 patients with IMSCT 22 patients with astrocytomas were identified and enrolled into this analysis. Demographic data, clinical symptoms, localization and extension of the tumor, resection rate as well as pre- and postoperative neurological status were obtained. Patients were followed-up clinically and by MRI. RESULTS: Complete resection rate was higher in cervically located tumors (9 of 10) compared to non-cervical tumors (7 of 12). Tumor extension (1-3 segments vs. > 3 segments involved) did not influence on the resection rate. Cervical tumors showed a trend for better postoperative functional outcome than non-cervical lesions (3 of 10 cervical but 6 of 12 non-cervical tumors deteriorated postoperatively). In tumors extending more than 3 segments postoperative worsening was significantly increased. CONCLUSIONS: The present study shows a better resectability and functional outcome for cervically located intramedullary astrocytomas. Tumors extending more than three segments deteriorated significantly. These findings may help for decision-making process and treatment of these tumors.

Progesterone Receptor Membrane Component 1 (PGRMC1) Modulates Tumour Progression, the Immune Microenvironment and the Response to Therapy in Glioblastoma.

Progesterone Receptor Membrane Component 1 (PGRMC1) is a tumour-promoting factor in several types of cancer but its role in brain tumours is poorly characterized thus far. Our study aimed to determine the effect of PGRMC1 on glioblastoma (GBM) pathophysiology using two independent cohorts of IDH wild-type GBM patients and stable knockdown GBM models. We found that high levels of PGRMC1 significantly predicted poor overall survival in both cohorts of GBM patients. PGRMC1 promoted the proliferation, anchorage-independent growth, and invasion of GBM cells. We identified Integrin beta-1 (ITGB1) and TCF 1/7 as potential members of the PGRMC1 pathway in vitro. The levels of ITGB1 and PGRMC1 also correlated in neoplastic tissues from GBM patients. High expression of PGRMC1 rendered GBM cells less susceptible to the standard GBM chemotherapeutic agent temozolomide but more susceptible to the ferroptosis inducer erastin. Finally, PGRMC1 enhanced Interleukin-8 production in GBM cells and promoted the recruitment of neutrophils. The expression of PGRMC1 significantly correlated with the numbers of tumour-infiltrating neutrophils also in tissues from GBM patients. In conclusion, PGRMC1 enhances tumour-related inflammation and promotes the progression of GBM. However, PGRMC1 might be a promising target for novel therapeutic strategies using ferroptosis inducers in this type of cancer.

Fight INflammation to Improve outcome after aneurysmal Subarachnoid HEmorRhage (FINISHER) trial: Study protocol for a randomized controlled trial.

RATIONALE: Aneurysmal subarachnoid hemorrhage (SAH) has high morbidity and mortality. While the primary injury results from the initial bleeding cannot currently be influenced, secondary injury through vasospasm and delayed cerebral ischemia worsens outcome and might be a target for interventions to improve outcome. To date, beside the aneurysm treatment to prevent re-bleeding and the administration of oral nimodipine, there is no therapy available, so novel treatment concepts are needed. Evidence suggests that inflammation contributes to delayed cerebral ischemia and poor outcome in SAH. Some studies suggest a beneficial effect of anti-inflammatory glucocorticoids, but there are no data from randomized controlled trials examining the efficacy of glucocorticoids. Therefore, current guidelines do not recommend the use of glucocorticoids in SAH. AIM: The Fight INflammation to Improve outcome after aneurysmal Subarachnoid HEmorRhage (FINISHER) trial aims to determine whether dexamethasone improves outcome in a clinically relevant endpoint in SAH patients. METHODS AND DESIGN: FINISHER is a multicenter, prospective, randomized, double-blinded, placebo-controlled clinical phase III trial which is testing the outcome and safety of anti-inflammatory treatment with dexamethasone in SAH patients. SAMPLE SIZE ESTIMATES: In all, 334 patients will be randomized to either dexamethasone or placebo within 48 h after SAH. The dexamethasone dose is 8 mg tds for days 1-7 and then 8 mg od for days 8-21. STUDY OUTCOME: The primary outcome is the modified Rankin Scale (mRS) at 6 months, which is dichotomized to favorable (mRS 0-3) versus unfavorable (mRS 4-6). DISCUSSION: The results of this study will provide the first phase III evidence as to whether dexamethasone improves outcome in SAH.

Real-World Evidence for Restorative Neurostimulation in Chronic Low Back Pain-a Consecutive Cohort Study.

BACKGROUND: Neuromuscular instability of the lumbar spine resulting from impaired motor control and degeneration of the multifidus muscle is a known root cause of refractory chronic low back pain (LBP). An implantable neurostimulation system that aims to restore multifidus motor control by stimulating the L2 medial branch of the dorsal ramus thereby relieving pain and reducing disability has demonstrated clinically significant benefits in the clinical trial setting. The 1-year results of a single-site real-world cohort study are presented. METHODS: This study recruited 44 consecutive patients with refractory, predominantly nociceptive axial chronic LBP, evidence of multifidus dysfunction, and no surgical indications or history of surgical intervention for chronic LBP. Each patient was implanted with a neurostimulation device. Pain (numeric rating scale), disability (Oswestry Disability Index), and quality of life (5-level EuroQol 5-Dimension) outcomes were collected at baseline and 3, 6, and 12 months after activation. RESULTS: Statistically significant improvements in pain, disability, and quality of life from baseline were seen at all assessment time points. At 12 months after activation, mean ± standard error of the mean numeric rating scale score was reduced from 7.6 ± 0.2 to 3.9 ± 0.4 (P < 0.001), Oswestry Disability Index score was reduced from 43.0 ± 2.8 to 25.8 ± 3.9 (P < 0.001), and 5-level EuroQol 5-Dimension index improved from 0.504 ± 0.034 to 0.755 ± 0.039 (P < 0.001). No lead migrations were observed. One patient required revision due to lead fracture. CONCLUSIONS: Restorative neurostimulation is a new treatment option for well-selected patients with refractory chronic LBP. Clinically meaningful improvements in pain, disability, and quality of life demonstrated in routine clinical practice are consistent with published results of controlled trials.

Geometric uncertainty in intracranial aneurysm rupture status discrimination: a two-site retrospective study.

OBJECTIVES: Assessing the risk associated with unruptured intracranial aneurysms (IAs) is essential in clinical decision making. Several geometric risk parameters have been proposed for this purpose. However, performance of these parameters has been inconsistent. This study evaluates the performance and robustness of geometric risk parameters on two datasets and compare it to the uncertainty inherent in assessing these parameters and quantifies interparameter correlations. METHODS: Two datasets containing 244 ruptured and unruptured IA geometries from 178 patients were retrospectively analysed. IAs were stratified by anatomical region, based on the PHASES score locations. 37 geometric risk parameters representing four groups (size, neck, non-dimensional, and curvature parameters) were assessed. Analysis included standardised absolute group differences (SADs) between ruptured and unruptured IAs, ratios of SAD to median relative uncertainty (MRU) associated with the parameters, and interparameter correlation. RESULTS: The ratio of SAD to MRU was lower for higher dimensional size parameters (ie, areas and volumes) than for one-dimensional size parameters. Non-dimensional size parameters performed comparatively well with regard to SAD and MRU. SAD was higher in the posterior anatomical region. Correlation of parameters was strongest within parameter (sub)groups and between size and curvature parameters, while anatomical region did not strongly affect correlation patterns. CONCLUSION: Non-dimensional parameters and few parameters from other groups were comparatively robust, suggesting that they might generalise better to other datasets. The data on discriminative performance and interparameter correlations presented in this study may aid in developing and choosing robust geometric parameters for use in rupture risk models.

VICTORIA: VIrtual neck Curve and True Ostium Reconstruction of Intracranial Aneurysms.

PURPOSE: For the status evaluation of intracranial aneurysms (IAs), morphological and hemodynamic parameters can provide valuable information. For their extraction, a separation of the aneurysm sac from its parent vessel is required that yields the neck curve and the ostium. However, manual and subjective neck curve and ostium definitions might lead to inaccurate IA assessments. METHODS: The research project VICTORIA was initiated, allowing users to interactively define the neck curve of five segmented IA models using a web application. The submitted results were qualitatively and quantitatively compared to identify the minimum, median and maximum aneurysm surface area. Finally, image-based blood flow simulations were carried out to assess the effect of variable neck curve definitions on relevant flow- and shear-related parameters. RESULTS: In total, 55 participants (20 physicians) from 18 countries participated in VICTORIA. For relatively simple aneurysms, a good agreement with respect to the neck curve definition was found. However, differences among the participants increased with increasing complexity of the aneurysm. Furthermore, it was observed that the majority of participants excluded any small arteries occurring in the vicinity of an aneurysm. This can lead to non-negligible deviations among the flow- and shear-related parameters, which need to be carefully evaluated, if quantitative analysis is desired. Finally, no differences between participants with medical and non-medical background could be observed. CONCLUSIONS: VICTORIAs findings reveal the complexity of aneurysm neck curve definition, especially for bifurcation aneurysms. Standardization appears to be mandatory for future sac-vessel-separations. For hemodynamic simulations a careful neck curve definition is crucial to avoid inaccuracies during the quantitative flow analysis.

Dynein Light Chain Protein Tctex1: A Novel Prognostic Marker and Molecular Mediator in Glioblastoma.

The purpose of this study was to determine the role of Tctex1 (DYNLT1, dynein light chain-1) in the pathophysiology of glioblastoma (GBM). To this end, we performed immunohistochemical analyses on tissues from GBM patients (n = 202). Tctex1 was additionally overexpressed in two different GBM cell lines, which were then evaluated in regard to their proliferative and invasive properties. We found that Tctex1 levels were significantly higher in GBM compared to healthy adjacent brain tissues. Furthermore, high Tctex1 expression was significantly associated with the short overall- (p = 0.002, log-rank) and progression-free (p = 0.028, log-rank) survival of GBM patients and was an independent predictor of poor overall survival in multivariate Cox-regression models. In vitro, Tctex1 promoted the metabolic activity, anchorage-independent growth and proliferation of GBM cells. This phenomenon was previously shown to occur via the phosphorylation of retinoblastoma protein (phospho-RB). Here, we found a direct and significant correlation between the levels of Tctex1 and phospho-RB (Ser807/801) in tissues from GBM patients (p = 0.007, Rho = 0.284, Spearman's rank). Finally, Tctex1 enhanced the invasiveness of GBM cells and the release of pro-invasive matrix metalloprotease 2 (MMP2). These findings indicate that Tctex1 promotes GBM progression and therefore might be a useful therapeutic target in this type of cancer.

AVM resection after radiation therapy--clinico-morphological features and microsurgical results.

A subgroup of patients initially treated by radiosurgery underwent surgical resection because of recurrent hemorrhage or neurological deterioration. In a retrospective study, we want to analyze the clinical features of these patients and evaluate the effect of microneurosurgery in such rare constellations. Moreover, we hope to find answers about failure of radiation therapy in these cases by correlation of radiobiological and histopathological data. Over a 16-year-period, eight patients with cerebral arteriovenous malformation (AVM) underwent surgical resection, who previously were treated by radiosurgery. The mean duration between radiation therapy and final resection was 7 years. Preoperative evaluation revealed Spetzler-Martin grade III (n=5) and IV (n=3) AVMs. Histological examination was achieved in all resected lesions. Mean neurological follow-up was 14 months. Indications for surgical resection were intracerebral hematoma, progressive neurological deficit, and epilepsy. In comparison to the initial angiographic study before radiation therapy, preoperative angiography revealed newly developed "en passant" feeding vessels and stenosis of the main venous drainage in some patients. The mean Rankin score for all patients was 2.75 before and 3.25 after surgical resection. Postoperatively, three patients (38%) developed neurological deterioration. Histological examination of the resected tissue revealed significant radiation-induced pathology in six patients. We did not see correlation between radiation doses and severity of histolopathological radiation-induced changes. Postoperative angiography confirmed total AVM resection in all patients. AVMs insufficiently treated by radiation bear an increased surgical risk. Often, angiographic studies revealed a more complicated morphology. Microsurgical resection was extremely challenging and led to unfavorable outcomes in many of the patients.

KLF4K409Q-mutated meningiomas show enhanced hypoxia signaling and respond to mTORC1 inhibitor treatment.

Meningioma represents the most common primary brain tumor in adults. Recently several non-NF2 mutations in meningioma have been identified and correlated with certain pathological subtypes, locations and clinical observations. Alterations of cellular pathways due to these mutations, however, have largely remained elusive. Here we report that the Krueppel like factor 4 (KLF4)-K409Q mutation in skull base meningiomas triggers a distinct tumor phenotype. Transcriptomic analysis of 17 meningioma samples revealed that KLF4K409Q mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4K409Q mutation induces HIF-1α through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1α targets. Finally, we demonstrate that KLF4K409Q mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4K409Q mediated upregulation of HIF pathways to the clinical and biological characteristics of these skull base meningiomas possibly opening new therapeutic avenues for this distinct meningioma subtype.

First in vivo visualization of the human subarachnoid space and brain cortex via optical coherence tomography.

The present work explores optical coherence tomography (OCT) as a suitable in vivo neuroimaging modality of the subarachnoid space (SAS). Patients (n = 26) with frontolateral craniotomy were recruited. The temporal and frontal arachnoid mater and adjacent anatomical structures were scanned using microscope-integrated three-dimensional OCT, (iOCT). Analysis revealed a detailed depiction of the SAS (76.9%) with delineation of the internal microanatomical structures such as the arachnoid barrier cell membrane (ABCM; 96.2%), trabecular system (50.2%), internal blood vessels (96.2%), pia mater (26.9%) and the brain cortex (96.2%). Orthogonal distance measuring was possible. The SAS showed a mean depth of 570 µm frontotemporal. The ABCM showed a mean depth of 74 µm frontotemporal. These results indicate that OCT provides a dynamic, non-invasive tool for real-time imaging of the SAS and adjacent anatomical structures at micrometer spatial resolution. Further studies are necessary to evaluate the value of OCT during microsurgical procedures.

Sex-specific clinicopathological significance of novel (Frizzled-7) and established (MGMT, IDH1) biomarkers in glioblastoma.

BACKGROUND: The Wnt receptor Frizzled-7 (FZD7) promotes tumor progression and can be currently targeted by monoclonal antibody therapy. Here, we determined the prognostic value of FZD7 for the overall survival of glioblastoma (GBM) patients, both as individual marker and taken in combination with the previously-described markers MGMT and IDH1. Additionally, we tested whether these markers (alone or in combination) exhibited sex-specific differences. RESULTS: High levels of FZD7 (FZD7high) associated with shorter survival in GBM patients; however, FZD7high was a significant predictor of poor survival only in male patients. Mutation of IDH1 significantly associated with longer survival in male but not female patients. Methylated MGMT promoter significantly associated with longer survival only in female patients. Combination of FZD7 with MGMT enhanced the prognostic accuracy and abrogated the sex differences observed upon single marker analysis. Combination of FZD7 with IDH1 was a significant predictor of survival in male GBM patients only. MATERIALS AND METHODS: Three independent cohorts of patients with primary GBM (n=120, n=108 and n=105, respectively) were included in this study. FZD7 and IDH1 were assessed by immunohistochemistry in tissue microarrays. MGMT promoter methylation was determined by methylation-specific polymerase chain reaction. Survival analysis was performed by Kaplan-Meier estimate, log-rank test and Cox proportional hazard regression. CONCLUSIONS: Our study identifies novel individual and combination markers with prognostic and, possibly, therapeutic relevance in GBM. Furthermore, our findings substantiate the importance of sexual dimorphism in this type of cancer.

The impact of neurophysiological intraoperative monitoring on surgical decisions: a critical analysis of 423 cases.

OBJECT: The aim of this observational clinical study was to analyze the impact of neurophysiological intraoperative monitoring (IOM) on the surgical procedure and to assess the benefits of such monitoring. METHODS: Data for 423 patients who underwent neurophysiological IOM with somatosensory evoked potentials and brainstem auditory evoked potentials during neurosurgical procedures were collected prospectively. The patients were classified into one of five groups according to the findings of IOM, the intervention following a monitoring alarm, and the patient's postoperative neurological condition. These groups were as follows: patients with true-positive findings with intervention (42 cases, 9.9%), those with true-positive findings without intervention (42 cases, 9.9%), those with false-positive findings (nine cases, 2.1%), those with false-negative findings (16 cases, 3.8%), and those with true-negative findings (314 cases, 74.2%). Different interventions followed an event identified with monitoring. These interventions were related to dissection in 17 cases, to perfusion pressure in 11, to a limitation of the surgical procedure in five, to vessel clipping in four, to vasospasm in three, and to retraction in one case. In one case the surgical procedure was abandoned. A critical analysis and cautious estimation of the interventions revealed that IOM was helpful in preventing a postoperative deficit in 5.2% of the monitored cases. CONCLUSIONS; For critical analysis of the benefits of IOM one must evaluate not only the findings of IOM and the patient's postoperative neurological condition but also the intraoperative findings and surgical interventions following a monitoring alarm. Evidence is presented that IOM is helpful in preventing a postoperative deficit.

Enhanced stability of somatosensory evoked potentials attained in the median nerve by using temporal electrodes for intraoperative recording in patients in the semisitting position.

OBJECT: Findings published in case reports indicate that monitoring of median nerve somatosensory evoked potentials (MN-SSEPs) is unreliable in patients who undergo surgery while in the semisitting position due to the occurrence of changes in the potentials that are unrelated to neurological damage. The present study was designed to test the hypothesis that in these patients MN-SSEPs are more stable when recording electrodes are placed over the temporal region. METHODS: In 30 patients who underwent surgery in the semisitting position, MN-SSEPs were recorded intraoperatively by using electrodes placed over the temporal region as well as those placed at conventional recording sites. The authors analyzed MN-SSEP amplitudes and latencies at different recording sites and at distinct steps of the monitoring procedure. In 10 of the 30 patients a clinically significant attenuation (> 50%) of MN-SSEP amplitude was observed at conventional recording sites and this was obviously not related to neurological damage. In contrast, no significant changes were observed in MN-SSEPs recorded from electrodes located over the temporal region. CONCLUSIONS: In patients who undergo surgery in the semisitting position, the use of additional recording electrodes placed over the temporal region makes intraoperative MN-SSEP monitoring less prone to false-positive alarms and thus enhances the reliability of intraoperative MN-SSEP monitoring.