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

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

KLF4(K409Q)-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 KLF4(K409Q) mutated tumors harbor an upregulation of hypoxia dependent pathways. Detailed in vitro investigation further showed that the KLF4(K409Q) mutation induces HIF-1 alpha through the reduction of prolyl hydroxylase activity and causes an upregulation of downstream HIF-1 alpha targets. Finally, we demonstrate that KLF4(K409Q) mutated tumors are susceptible to mTOR inhibition by Temsirolimus. Taken together, our data link the KLF4(K409Q) 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

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