Radiosynthesis and Preclinical Evaluation of m-[18F]FET and [18F]FET-OMe as Novel [18F]FET Analogs for Brain Tumor Imaging.

O-([18F]Fluoroethyl)-l-tyrosine ([18F]FET) is actively transported into the brain and cancer cells by LAT1 and possibly other amino acid transporters, which enables brain tumor imaging by positron emission tomography (PET). However, tumor delivery of this probe in the presence of competing amino acids may be limited by a relatively low affinity for LAT1. The aim of the present work was to evaluate the meta-substituted [18F]FET analog m-[18F]FET and the methyl ester [18F]FET-OMe, which were designed to improve tumor delivery by altering the physicochemical, pharmacokinetic, and/or transport properties. Both tracers could be prepared with good radiochemical yields of 41-56% within 66-90 min. Preclinical evaluation with [18F]FET as a reference tracer demonstrated reduced in vitro uptake of [18F]FET-OMe by U87 glioblastoma cells and no advantage for in vivo tumor imaging. In contrast, m-[18F]FET showed significantly improved in vitro uptake and accelerated in vivo tumor accumulation in an orthotopic glioblastoma model. As such, our work identifies m-[18F]FET as a promising alternative to [18F]FET for brain tumor imaging that deserves further evaluation with regard to its transport properties and in vivo biodistribution.

Prospective evaluation of flow-regulated valves for idiopathic normal pressure hydrocephalus: 1-year results.

OBJECTIVE: Overdrainage and frequent reprogramming are common problems with programmable valves after ventriculoperitoneal shunt surgery for idiopathic normal pressure hydrocephalus (iNPH). Non-adjustable, flow-regulated valves offer a potential solution to these problems, but there is limited data on their efficacy. This study will evaluate neurological improvement and overdrainage rates within one year of treatment with a flow-regulated valve. PATIENTS AND METHODS: This prospective study analyzes 45 iNPH patients (median age: 73 years) treated with a flow-regulated valve. Clinical evaluations were performed at baseline, postoperatively, and at 3, 6, and 12 months after surgery. The primary efficacy endpoint was improvement of at least 5 points on the iNPH grading scale at follow-up. The safety endpoint was radiographic evidence of overdrainage. RESULTS: All patients presented with gait disturbance, 35 (78 %) had cognitive impairment, and 35 (78 %) had urinary incontinence. The median duration of symptoms was 24 months. The total iNPH score improved in 33/41 (81 %) at 3 months, in 29/34 (85 %) at 6 months, and in 22/29 (64 %) at 12 months. Overall, 40/45 (89 %) patients had a significant improvement on the iNPH scale. Secondary worsening of symptoms after initial improvement was observed in 5 (11 %) patients. Overdrainage occurred in one patient (2 %) requiring surgical evacuation. CONCLUSION: Treatment of iNPH patients with flow-regulated valves resulted in a good neurological outcome with minimal rates of overdrainage. These results are encouraging and justify the clinical use of these valve types.

Sellar Melanoma With Lung Metastasis: A Case Report.

We report the case of an 81-year-old patient with no pre-existing medical conditions who presented with a one-week history of progressive horizontal diplopia. Contrast-enhanced brain magnetic resonance imaging showed a heterogeneous sellar mass with the infiltration of the cavernous sinus and sella. Hormone levels were within normal limits. Considering an endocrine inactive pituitary adenoma, the patient underwent transsphenoidal resection. After surgery, the preoperative symptoms completely resolved. Histopathologic examination of the tumor specimen revealed melanoma. Since the patient had no history of cancer, an extensive staging workup was performed, which revealed multiple lung metastases. However, no primary tumor was found. We recommended adjuvant brain irradiation and chemo- and immunotherapy, but the patient refused further oncological treatment and died five months after surgery. Reported cases of sellar melanoma are rare, and the combination of sellar melanoma and lung metastasis without a cutaneous primary is unique. Although rare, malignant lesions of the sella must be considered in the differential diagnosis, especially in cases with rapid onset of symptoms.

Comparative Analysis of the Low-Profile Acclino Stent and the Enterprise Stent for the Treatment of Unruptured Intracranial Aneurysms.

OBJECTIVE: In preliminary studies, advanced intracranial stents appear to have a favorable safety profile for intracranial aneurysm treatment. This dual-center study is a head-to-head comparison of the low-profile Acandis Acclino stent (a third-generation stent) and the first- and second-generation Enterprise stent. METHODS: Patients who underwent stent-assisted coiling with either the Enterprise or the Acclino stent for unruptured aneurysms during an 8-year period were enrolled and compared for complications, clinical outcomes, and angiographic results. Primary outcome measures were ischemic stroke rate and mid-term complete occlusion rate. Propensity score adjustment was performed to account for small differences between the groups. RESULTS: Enterprise and Acclino stents were used in 48 cases each. The overall rate of thrombotic complications was higher in the Enterprise group than in the Acclino group (20.8% vs. 4.2%, HR: 6.6, 95%CI: 2.2-20.0, P = 0.01, adjusted P < 0.01), which translated into a higher rate of major ischemic stroke after Enterprise treatment (6.3% vs. 0%, HR: 2.1, 95%CI: 1.8-2.4, P = 0.08, adjusted P < 0.01). Mid-term and long-term angiographic follow-up showed complete occlusion rates of 83.3% and 75.0% for Enterprise and 89.2% and 75.9% for Acclino (both P > 0.05). Retreatment rates were 10.4% in the Enterprise group and 4.2% in the Acclino group (P = 0.42, adjusted P = 0.10). CONCLUSIONS: The results indicate a favorable safety profile of the Acclino over the Enterprise, justifying the use of advanced stent systems in clinical practice. However, further comparative studies of the Acclino and other competing stent systems are needed to draw a definitive conclusion on the state of stent-assisted coiling.

Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas.

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway  in neoplasia.

Safety and efficacy of the fourth-generation Acandis Acclino flex plus stent for the treatment of complex intracranial aneurysms.

OBJECTIVE: The low-profile Acandis Acclino flex plus (AFP) is a fourth-generation laser-cut microstent with a flexible structure designed for the treatment of a wide variety of aneurysms. We report our single-center experience with this device in the treatment of complex aneurysms. METHODS: Twenty-eight patients were treated with the Acclino flex plus for 28 aneurysms. Aneurysm characteristics, technical success, complications, clinical outcome, and angiographic results were retrospectively analyzed. RESULTS: The cohort included 8 unruptured untreated aneurysms, 9 unruptured recurrent aneurysms, and 12 ruptured aneurysms with aneurysm diameters ranging from 3 to 23 mm. The anterior communicating artery was the most common location (52%). Stent deployment was successful in 28 cases (97%) with an average of 1.3 stents per aneurysm. The overall procedural complication rate was 17%, including 2 (6.8%) major clinical events (one ischaemic stroke and one aneurysm perforation) and one (3.4%) minor clinical event (one seizure). Angiographic results of 23 aneurysms at a mean of 6 months were complete occlusion in 74%, neck remnants in 13% and aneurysm remnants in 13%. Three patients were retreated. CONCLUSIONS: Given the complexity of the aneurysms, the use of the Acclino flex plus was feasible and associated with a favourable safety and efficacy profile. Further studies are needed to evaluate Acclino flex plus in other aneurysm subsets and to define its role in endovascular aneurysm treatment.

Cost-effectiveness of WEB Embolization, Coiling and Stent-assisted Coiling for the Treatment of Unruptured Intracranial Aneurysms.

PURPOSE: Information about the cost-effectiveness of a certain treatment is relevant for decision-making and healthcare providers. This study compares the cost-effectiveness of the novel Woven Endobridge (WEB) for intracranial aneurysm treatment with conventional coiling and stent-assisted coiling (SAC) from the perspective of the German Statutory Health Insurance. METHODS: A patient-level simulation was constructed to simulate 55-year-old patients with an unruptured middle cerebral artery aneurysm (size: 3-11 mm) considering WEB treatment, coiling or SAC in terms of morbidity, angiographic outcome, retreatment, procedural and rehabilitation costs and rupture rates. Incremental cost-effectiveness ratios (ICERs) were calculated as costs per quality-adjusted life years (QALYs) and costs per year with neurologic morbidity avoided. Uncertainty was explored with deterministic and probabilistic sensitivity analyses. The majority of data were obtained from prospective multi-center studies and meta-analyses of non-randomized studies. RESULTS: In the base case, lifetime QALYs were 13.24 for the WEB, 12.92 for SAC and 12.68 for coiling. Lifetime costs were 20,440 € for the WEB, 23,167 € for SAC, and 8200 € for coiling. Compared to coiling, the ICER for the WEB was 21,826 €/QALY, while SAC was absolutely dominated by WEB. Probabilistic sensitivity analysis revealed that at a willingness-to-pay of ≥ 30,000 €/QALY, WEB was the preferred treatment. Deterministic sampling showed that the discount rate, material costs and retreatment rates had the largest impact on the ICERs. CONCLUSION: The novel WEB showed at least comparable cost-effectiveness to SAC for treatment of broad-based unruptured aneurysms. Considering all three modalities, coiling had the least costs; however this modality is often not appropriate for the treatment of wide-necked aneurysms.

Angiographic Characteristics Associated with Rupture of Small Intracranial Aneurysms.

OBJECTIVE: Contrary to previous assumptions, there is increasing evidence that small intracranial aneurysms carry a relevant risk of rupture. The aim of this study was to identify angiographic characteristics of small ruptured aneurysms ≤7 mm and to evaluate their significance for clinical decision making. METHODS: A total of 385 patients with 149 unruptured and 236 ruptured intracranial aneurysms were retrospectively compared. Two- and three-dimensional digital subtraction angiography was used to determine aneurysm location, various size parameters, angulations, and morphology, as well as parent artery diameter. RESULTS: Aneurysms of the anterior communicating artery, the posterior inferior cerebellar artery, and the internal carotid artery terminus had a significantly increased prevalence among ruptured aneurysms. Ruptured aneurysms were characterized by a significantly larger aneurysm height (area under the curve [AUC] 0.60, P < 0.01) and aneurysm inclination angle (AUC 0.61, P = 0.02) in addition to a smaller dome (AUC 0.44, P = 0.02) and neck width (AUC 0.38, P < 0.01). Calculation of size ratios increases the predictive value for aneurysm rupture, with AUC values of 0.77 for aspect ratio (P < 0.01) and 0.76 for size ratio (P < 0.01). Aneurysm morphology was not a significant factor after multivariable adjustment (P = 0.20). Arterial hypertension was the only clinical risk factor significantly associated with rupture (P < 0.01). CONCLUSIONS: Of the numerous factors associated with aneurysm rupture, we propose aneurysmal location, aspect ratio (cut-off: 1.5), and aneurysm inclination angle as the most important morphological factors for assessing the rupture risk of small aneurysms because these factors have high AUC values and are robust to changes after rupture.

Intraoperative microscopic autofluorescence detection and characterization in brain tumors using stimulated Raman histology and two-photon fluorescence.

Introduction: The intrinsic autofluorescence of biological tissues interferes with the detection of fluorophores administered for fluorescence guidance, an emerging auxiliary technique in oncological surgery. Yet, autofluorescence of the human brain and its neoplasia is sparsely examined. This study aims to assess autofluorescence of the brain and its neoplasia on a microscopic level by stimulated Raman histology (SRH) combined with two-photon fluorescence. Methods: With this experimentally established label-free microscopy technique unprocessed tissue can be imaged and analyzed within minutes and the process is easily incorporated in the surgical workflow. In a prospective observational study, we analyzed 397 SRH and corresponding autofluorescence images of 162 samples from 81 consecutive patients that underwent brain tumor surgery. Small tissue samples were squashed on a slide for imaging. SRH and fluorescence images were acquired with a dual wavelength laser (790 nm and 1020 nm) for excitation. In these images tumor and non-tumor regions were identified by a convolutional neural network that reliably differentiates between tumor, healthy brain tissue and low quality SRH images. The identified areas were used to define regions.of- interests (ROIs) and the mean fluorescence intensity was measured. Results: In healthy brain tissue, we found an increased mean autofluorescence signal in the gray (11.86, SD 2.61, n=29) compared to the white matter (5.99, SD 5.14, n=11, p<0.01) and in the cerebrum (11.83, SD 3.29, n=33) versus the cerebellum (2.82, SD 0.93, n=7, p<0.001), respectively. The signal of carcinoma metastases, meningiomas, gliomas and pituitary adenomas was significantly lower (each p<0.05) compared to the autofluorescence in the cerebrum and dura, and significantly higher (each p<0.05) compared to the cerebellum. Melanoma metastases were found to have a higher fluorescent signal (p<0.01) compared to cerebrum and cerebellum. Discussion: In conclusion we found that autofluorescence in the brain varies depending on the tissue type and localization and differs significantly among various brain tumors. This needs to be considered for interpreting photon signal during fluorescence-guided brain tumor surgery.

Release of Hyaluronan in Aneurysmal Subarachnoid Hemorrhage and Cerebral Vasospasm: A Pilot Study Indicating a Shedding of the Endothelial Glycocalyx.

BACKGROUND: This pilot study investigated plasma concentrations of hyaluronan, heparan sulfate, and syndecan-1 as possible biomarkers for glycocalyx integrity after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: Daily blood samples for biomarker assay were obtained in aSAH patients on the intensive care unit stay and compared with samples from a historic cohort of 40 healthy controls. In post hoc subgroup analyses in patients with and without cerebral vasospasm, we explored the influence of aSAH-related cerebral vasospasm on biomarker levels. RESULTS: A total of 18 aSAH patients and 40 historic controls were included in the study. Median (interquartile range) plasma levels of hyaluronan were higher in aSAH patients compared with controls (131 [84 to 179] vs. 92 [82 to 98] ng/mL, respectively; P=0.009), whereas heparan sulfate (mean±SD: 754±428 vs. 1329±316 ng/mL; P<0.001) and syndecan-1 (median: 23 [17 to 36] vs. 30 [23 to 52] ng/mL; P=0.02) levels were lower. Patients who developed vasospasm had significantly higher median hyaluronan concentrations at day 7 (206 [165 to 288] vs. 133 [108 to 164] ng/mL, respectively; P=0.009) and at day of first vasospasm detection (203 [155 to 231] vs. 133 [108 to 164] ng/mL, respectively; P=0.01) compared with those without vasospasm. Heparan sulfate and syndecan-1 concentrations were similar in patients with and without vasospasm. CONCLUSIONS: The increased plasma concentrations of hyaluronan after aSAH suggest selective shedding of this component of the glycocalyx. Increased levels of hyaluronan in patients with cerebral vasospasm, underlines a potential role for hyaluronan in vasospasm processes.

Glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA): a molecularly distinct brain tumor type with recurrent NTRK gene fusions.

Glioneuronal tumors are a heterogenous group of CNS neoplasms that can be challenging to accurately diagnose. Molecular methods are highly useful in classifying these tumors-distinguishing precise classes from their histological mimics and identifying previously unrecognized types of tumors. Using an unsupervised visualization approach of DNA methylation data, we identified a novel group of tumors (n = 20) that formed a cluster separate from all established CNS tumor types. Molecular analyses revealed ATRX alterations (in 16/16 cases by DNA sequencing and/or immunohistochemistry) as well as potentially targetable gene fusions involving receptor tyrosine-kinases (RTK; mostly NTRK1-3) in all of these tumors (16/16; 100%). In addition, copy number profiling showed homozygous deletions of CDKN2A/B in 55% of cases. Histological and immunohistochemical investigations revealed glioneuronal tumors with isomorphic, round and often condensed nuclei, perinuclear clearing, high mitotic activity and microvascular proliferation. Tumors were mainly located supratentorially (84%) and occurred in patients with a median age of 19 years. Survival data were limited (n = 18) but point towards a more aggressive biology as compared to other glioneuronal tumors (median progression-free survival 12.5 months). Given their molecular characteristics in addition to anaplastic features, we suggest the term glioneuronal tumor with ATRX alteration, kinase fusion and anaplastic features (GTAKA) to describe these tumors. In summary, our findings highlight a novel type of glioneuronal tumor driven by different RTK fusions accompanied by recurrent alterations in ATRX and homozygous deletions of CDKN2A/B. Targeted approaches such as NTRK inhibition might represent a therapeutic option for patients suffering from these tumors.

Impact of the SARS-CoV-2 pandemic on the survival of patients with high-grade glioma and best practice recommendations.

The severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) has changed the clinical day-to-day practice. The aim of this study was to evaluate the impact of the pandemic on patients with high-grade glioma (HGG) as well as to derive best practice recommendations. We compared a multi-institutional cohort with HGG (n = 251) from 03/2020 to 05/2020 (n = 119) to a historical cohort from 03/2019 to 05/2019 (n = 132). The endpoints were outcome (progression-free survival (PFS) and overall survival (OS)) as well as patterns of care and time intervals between treatment steps. The median OS for WHO grade 4 gliomas was 12 months in 2019 (95% Confidence Interval 9.7-14.3 months), and not reached in 2020 (p = .026). There were no other significant differences in the Kaplan-Meier estimates for OS and PFS between cohorts of 2019 and 2020, neither did stratification by WHO grade reveal any significant differences for OS, PFS or for patterns of care. The time interval between cranial magnetic resonance imaging (cMRI) and biopsy was significantly longer in 2020 cohort (11 versus 21 days, p = .031). Median follow-up was 10 months (range 0-30 months). Despite necessary disease containment policies, it is crucial to ensure that patients with HGG are treated in line with the recent guidelines and standard of care (SOC) algorithms. Therefore, we strongly suggest pursuing no changes to SOC treatment, a timely diagnosis and treatment with short time intervals between first symptoms, initial diagnosis, and treatment, as well as a guideline-based cMRI follow-up.

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.

Novel rapid intraoperative qualitative tumor detection by a residual convolutional neural network using label-free stimulated Raman scattering microscopy.

Determining the presence of tumor in biopsies and the decision-making during resections is often dependent on intraoperative rapid frozen-section histopathology. Recently, stimulated Raman scattering microscopy has been introduced to rapidly generate digital hematoxylin-and-eosin-stained-like images (stimulated Raman histology) for intraoperative analysis. To enable intraoperative prediction of tumor presence, we aimed to develop a new deep residual convolutional neural network in an automated pipeline and tested its validity. In a monocentric prospective clinical study with 94 patients undergoing biopsy, brain or spinal tumor resection, Stimulated Raman histology images of intraoperative tissue samples were obtained using a fiber-laser-based stimulated Raman scattering microscope. A residual network was established and trained in ResNetV50 to predict three classes for each image: (1) tumor, (2) non-tumor, and (3) low-quality. The residual network was validated on images obtained in three small random areas within the tissue samples and were blindly independently reviewed by a neuropathologist as ground truth. 402 images derived from 132 tissue samples were analyzed representing the entire spectrum of neurooncological surgery. The automated workflow took in a mean of 240 s per case, and the residual network correctly classified tumor (305/326), non-tumorous tissue (49/67), and low-quality (6/9) images with an inter-rater agreement of 89.6% (κ = 0.671). An excellent internal consistency was found among the random areas with 90.2% (Cα = 0.942) accuracy. In conclusion, the novel stimulated Raman histology-based residual network can reliably detect the microscopic presence of tumor and differentiate from non-tumorous brain tissue in resection and biopsy samples within 4 min and may pave a promising way for an alternative rapid intraoperative histopathological decision-making tool.

Initial clinical experience with N-hexyl cyanoacrylate for neuroendovascular embolization.

OBJECTIVE: To report our initial clinical experience with N-hexyl cyanoacrylate (NHCA), a novel liquid agent for neurovascular embolization. METHODS: Four paragangliomas were treated with percutaneous embolization using NHCA as the sole embolic material. In one dural arteriovenous fistula (dAVF), NHCA was used in combination with other embolic materials. Procedural specifics, complications and angiographic results were retrospectively evaluated. RESULTS: Total or subtotal devascularization was obtained in 3 of the 4 paragangliomas. In the largest tumor, only partial devascularization could be achieved. The dAVF was completely occluded. Catheter entrapment did not occur. After dAVF treatment, the patient had an asymptomatic lacunar infarction, while there was no procedural morbidity related to paraganglioma treatment. CONCLUSIONS: In this series, neurovascular embolization with NHCA was feasible and effective. It may be particularly beneficial for small and tortuous vessels that require low-profile catheterization and a slow and controlled polymerization. Further studies are necessary to prove the benefits of NHCA over established embolic agents.

Convenient PET-tracer production via SuFEx 18F-fluorination of nanomolar precursor amounts.

Recently, a protocol for radiolabeling of aryl fluorosulfates ("SuFEx click radiolabeling") using ultrafast 18F/19F isotopic exchange has been reported. Although promising, the original procedure turned out to be rather inefficient. However, systematic optimization of the reaction parameters allowed for development of a robust method for SuFEx radiolabeling which obviates the need for azeotropic drying, base addition and HPLC purification. The developed protocol enabled efficient 18F-fluorination of low nanomolar amounts of aryl fluorosulfates in highly diluted solution (micromolar concentrations). It was successfully used to prepare a series of 29 18F-fluorosulfurylated phenols - including modified ezetimibe, α-tocopherol and etoposide, the two tyrosine derivatives Boc-Tyr([18F]FS)-OMe and H-Tyr([18F]FS)-OMe, the FAP-specific ligand [18F]FS-UAMC1110, and the DPA-714 analog [18F]FS-DPA - in fair to excellent yields. Preliminary evaluation demonstrated sufficient in vivo stability of radiofluorinated electron rich or neutral {Boc-Tyr([18F]FS)-OMe), H-Tyr([18F]FS)-OMe and [18F]FS-DPA} aryl fluorosulfates. Furthermore, [18F]FS-DPA was identified as a promising tracer for visualization of TSPO expression.

Expression of ENO1 Is Up-regulated in Low-grade Glioma and Positively Correlated With Meningioma Grade.

BACKGROUND: α-Enolase (ENO1) is a glycolytic enzyme involved in the Warburg effect which cancer cells utilize to satisfy their higher need for nutrients. Up-regulation of ENO1 has been detected in several tumor types, including melanoma and endometrial, gastric and colorectal cancer. In these tumors, ENO1 may function as prognostic marker. Therefore, it was our interest to determine the expression of ENO1 in glioma and meningioma and whether chemotherapy of glioma alters ENO1 expression. MATERIAL AND METHODS: Tumor samples and control tissues were obtained during neurosurgery. All tumor samples were grouped according to WHO classification. Quantitative polymerase chain reaction and western blot were used to detect the expression of ENO1 in glioma and meningioma. All assays were carried out in triplicates; ß-actin was used as a housekeeping gene. For western blots, all samples were incubated with mouse monoclonal anti-ENO1 followed by secondary horseradish peroxidase-linked anti-mouse antibody, with ß-actin as a loading control. Immunofluorescence (n=33) was performed to determine the presence of ENO1 in tumor and control tissues using primary antibody to ENO1 and anti-Cy3 as secondary antibody. RESULTS: The expression of ENO1 mRNA was significantly higher in the control group compared to glioma (p<0.0001) and its protein was also significantly up-regulated in low-grade glioma in comparison to high-grade (p<0.0001). ENO1 expression in grade II and III meningiomas was increased compared to grade I (p=0.016 and p=0.0010, respectively) and in grade III compared to grade II (p=0.0363). CONCLUSION: Our findings suggest that ENO1 might be a marker for meningioma progression and that ENO1 is up-regulated in low-grade glioma.

Death Receptor 6 as a Prognostic Marker in Low-grade Glioma.

BACKGROUND/AIM: Low-grade gliomas (LGG) are heterogenous tumours, causing variable survivals in patients. Identifying molecular markers for a more accurate prognosis is, therefore, important. Since death receptor 6 (DR6) is up-regulated in gliomas and shows an aberrant signalling network, we tested its suitability as a prognostic marker. MATERIALS AND METHODS: DR6 was investigated in patient samples via PCR and western blot. Clinical data were analysed and compared to The Cancer Genome Atlas (TCGA) 'brain lower grade glioma' dataset. RESULTS: DR6 was found to be enhanced in LGG and its expression increased in recurrent LGG. The receptor showed a protective effect in primary LGG with a significantly elongated progression-free survival that was confirmed in the TCGA study. This effect was reversed in relapsed LGG in which cases with high DR6 expression reveal a shorter overall survival. CONCLUSION: DR6 is an interesting candidate for further studies regarding its effect as a prognostic marker, playing an opposing role in primary and relapsed LGG.

Evaluation of 3-l- and 3-d-[18F]Fluorophenylalanines as PET Tracers for Tumor Imaging.

PURPOSE: The preclinical evaluation of 3-l- and 3-d-[18F]FPhe in comparison to [18F]FET, an established tracer for tumor imaging. METHODS: In vitro studies were conducted with MCF-7, PC-3, and U87 MG human tumor cell lines. In vivo µPET studies were conducted in healthy rats with/without the inhibition of peripheral aromatic l-amino acid decarboxylase by benserazide pretreatment (n = 3 each), in mice bearing subcutaneous MCF-7 or PC-3 tumor xenografts (n = 10), and in rats bearing orthotopic U87 MG tumor xenografts (n = 14). Tracer accumulation was quantified by SUVmax, SUVmean and tumor-to-brain ratios (TBrR). RESULTS: The uptake of 3-l-[18F]FPhe in MCF-7 and PC-3 cells was significantly higher relative to [18F]FET. The uptake of all three tracers was significantly reduced by the suppression of amino acid transport systems L or ASC. 3-l-[18F]FPhe but not 3-d-[18F]FPhe exhibited protein incorporation. In benserazide-treated healthy rats, brain uptake after 42-120 min was significantly higher for 3-d-[18F]FPhe vs. 3-l-[18F]FPhe. [18F]FET showed significantly higher uptake into subcutaneous MCF-7 tumors (52-60 min p.i.), while early uptake into orthotopic U87 MG tumors was significantly higher for 3-l-[18F]FPhe (SUVmax: 3-l-[18F]FPhe, 107.6 ± 11.3; 3-d-[18F]FPhe, 86.0 ± 4.3; [18F]FET, 90.2 ± 7.7). Increased tumoral expression of LAT1 and ASCT2 was confirmed immunohistologically. CONCLUSION: Both novel tracers enable accurate tumor delineation with an imaging quality comparable to [18F]FET.

Propensity score-adjusted analysis on stent-assisted coiling versus coiling alone for ruptured intracranial aneurysms.

Stent-assisted coiling (SAC) for ruptured intracranial aneurysms (RIAs) remains controversial due to an inherent risk of potential thromboembolic and hemorrhagic complications. We compared SAC and coiling alone for the management of RIAs using propensity score-adjustment. Sixty-four patients treated by SAC and 220 by stand-alone coiling were retrospectively reviewed and compared using inverse probability of treatment weighting (IPTW) with propensity scores. Functional outcome, procedure-related and overall complications and angiographic results were analyzed. Aneurysms treated by SAC had a larger diameter, a wider neck and were more frequently located at the posterior circulation. SAC had a higher risk for thromboembolic complications (17.2% vs. 7.7%, p = 0.025), however, this difference did not persist in the IPTW analysis (OR 1.2, 95% CI 0.7-2.3, adjusted p = 0.458). In the adjusted analysis, rates of procedural cerebral infarction (p = 0.188), ventriculostomy-related hemorrhage (p = 0.584), in-hospital mortality (p = 0.786) and 6-month favorable functional outcome (p = 0.471) were not significantly different between the two groups. SAC yielded a higher complete occlusion (80.0% vs. 67.2%, OR 3.2, 95% CI 1.9-5.4, p < 0.001) and a lower recanalization rate (17.5% vs. 26.1%, OR 0.3, 95% CI 0.2-0.6, p < 0.001) than stand-alone coiling at 6-month follow-up. In conclusion, SAC of large and wide-necked RIAs provided higher aneurysm occlusion and similar clinical outcome, when compared to stand-alone coiling.