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.

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 weekend effect on outcome after microsurgical clipping of ruptured intracranial aneurysms.

BACKGROUND: The "weekend effect" describes the assumption that weekend and/or on-call duty admission of emergency patients is associated with increased morbidity and mortality rates. For aneurysmal subarachnoid hemorrhage, we investigated, whether presentation out of regular working hours and microsurgical clipping at nighttime correlates with worse patient outcome. METHODS: This is a retrospective review of consecutive patients that underwent microsurgical clipping of an acutely ruptured aneurysm at our institution between 2010 and 2019. Patients admitted during (1) regular working hours (Monday-Friday, 08:00-17:59) and (2) on-call duty and microsurgical clipping performed during (a) daytime (Monday-Sunday, 08:00-17:59) and (b) nighttime were compared regarding the following outcome parameters: operation time, treatment-related complications, vasospasm, functional outcome, and angiographic results. RESULTS: Among 157 enrolled patients, 104 patients (66.2%) were admitted during on-call duty and 48 operations (30.6%) were performed at nighttime. Admission out of regular hours did not affect cerebral infarction (p = 0.545), mortality (p = 0.343), functional outcome (p = 0.178), and aneurysm occlusion (p = 0.689). Microsurgical clipping at nighttime carried higher odds of unfavorable outcome at discharge (OR: 2.3, 95%CI: 1.0-5.1, p = 0.039); however, there were no significant differences regarding the remaining outcome parameters. After multivariable adjustment, clipping at nighttime did not remain as independent prognosticator of short-term outcome (OR: 2.1, 95%CI: 0.7-6.2, p = 0.169). CONCLUSIONS: Admission out of regular working hours and clipping at nighttime were not independently associated with poor outcome. The adherence to standardized treatment protocols might mitigate the "weekend effect."

Fully automated detection and segmentation of meningiomas using deep learning on routine multiparametric MRI.

OBJECTIVES: Magnetic resonance imaging (MRI) is the method of choice for imaging meningiomas. Volumetric assessment of meningiomas is highly relevant for therapy planning and monitoring. We used a multiparametric deep-learning model (DLM) on routine MRI data including images from diverse referring institutions to investigate DLM performance in automated detection and segmentation of meningiomas in comparison to manual segmentations. METHODS: We included 56 of 136 consecutive preoperative MRI datasets [T1/T2-weighted, T1-weighted contrast-enhanced (T1CE), FLAIR] of meningiomas that were treated surgically at the University Hospital Cologne and graded histologically as tumour grade I (n = 38) or grade II (n = 18). The DLM was trained on an independent dataset of 249 glioma cases and segmented different tumour classes as defined in the brain tumour image segmentation benchmark (BRATS benchmark). The DLM was based on the DeepMedic architecture. Results were compared to manual segmentations by two radiologists in a consensus reading in FLAIR and T1CE. RESULTS: The DLM detected meningiomas in 55 of 56 cases. Further, automated segmentations correlated strongly with manual segmentations: average Dice coefficients were 0.81 ± 0.10 (range, 0.46-0.93) for the total tumour volume (union of tumour volume in FLAIR and T1CE) and 0.78 ± 0.19 (range, 0.27-0.95) for contrast-enhancing tumour volume in T1CE. CONCLUSIONS: The DLM yielded accurate automated detection and segmentation of meningioma tissue despite diverse scanner data and thereby may improve and facilitate therapy planning as well as monitoring of this highly frequent tumour entity. KEY POINTS: • Deep learning allows for accurate meningioma detection and segmentation • Deep learning helps clinicians to assess patients with meningiomas • Meningioma monitoring and treatment planning can be improved.

Does Meningioma Volume Correlate With Clinical Disease Manifestation Irrespective of Histopathologic Tumor Grade?

OBJECTIVES: The aim of the study was to investigate the association between meningioma volume and the occurrence of clinic-radiologic signs of tumor aggressiveness. For volumetric approximation, the authors evaluated the method of semiautomatic image segmentation at hand of high-resolution MRI-image sequences. METHODS: ITK-SNAP was utilized for semiautomatic image segmentation of 58 gadolinium-contrast enhanced T1-weighted thin-slice MRI datasets for volumetric analysis. Furthermore, multimodal imaging datasets (including T2, FLAIR, T1) were evaluated for radiological biomarkers of aggressiveness and growth potential. Thereby generated data was checked for association with retrospectively collected data points. RESULTS: Location (P = 0.001), clinical disease manifestation (P = 0.033), peritumoral edema (P = 0.038), tumor intrinsic cystic degeneration (P = 0.007), three-dimensional complexity (P = 0.022), and the presence of meningioma mass effect (P = 0.001) were statistically associated with higher tumor volumes. There was no association between higher tumor volumes and histopathological tumor grade. CONCLUSION: The size of a meningioma does not seem to reliably predict tumor grade. Growth potential seems to be influenced by tumor location. Higher tumor volumes were significantly associated with the occurrence of clinical symptoms.

Vein Graft Interposition: A Training Model Using Gradually Thawed Cryopreserved Vessels.

INTRODUCTION: Microsurgical interposition of vein grafts is an extraordinarily filigree surgical technique, which requires both sound theoretical knowledge and solid manual skills. Although there are a large number of training models, the majority of these are either relatively expensive, technically complex, or employ synthetic materials with poor resemblance to human tissue. The authors' model allows training of ex vivo vein graft interposition on gradually thawed cryopreserved vessels and it, therefore, is cost-efficient and readily available when needed. Furthermore, it respects the 3R-principle (Reduce-Refine-Replace), as it is based on rat cadaveric vessels. METHODS: Three trainees with basic microsurgical experience, but without prior performance of vein graft interpositioning, were chosen to perform 20 femoral vein graft (5 mm) interpositions into femoral artery defects. The patency and leakage rate served as qualitative variable and operation time as a quantitative variable for efficiency control. RESULTS: For the first half of trials, the trainees had a patency failure rate of 50% and for the second half a rate of 13.3%. The leakage rate noticeably decreased from 44.4% in the first half of trials to 10% in the second half. Although the trainees needed 60 minutes on average for their first 10 trials, they improved to 51 minutes for their last 10 anastomoses. CONCLUSION: The authors' microsurgical model offers a simple, low-cost simulation training, specifically designed for learning of vein graft interposition into arterial defects. The model is associated with a high learning curve, based on an objective control of the anastomoses by assessment of the patency, leakage, and operation time.

Inhibition of the PI3K but not the MEK/ERK pathway sensitizes human glioma cells to alkylating drugs.

BACKGROUND: Intrinsic chemoresistance of glioblastoma (GBM) is frequently owed to activation of the PI3K and MEK/ERK pathways. These signaling cascades are tightly interconnected however the quantitative contribution of both to intrinsic resistance is still not clear. Here, we aimed at determining the activation status of these pathways in human GBM biopsies and cells and investigating the quantitative impact of both pathways to chemoresistance. METHODS: Receptor tyrosine kinase (RTK) pathways in temozolomide (TMZ) treatment naive or TMZ resistant human GBM biopsies and GBM cells were investigated by proteome profiling and immunoblotting of a subset of proteins. Resistance to drugs and RTK pathway inhibitors was assessed by MTT assays. Apoptotic rates were determined by Annexin V staining and DNA damage with comet assays and immunoblotting. RESULTS: We analyzed activation of RTK pathways by proteome profiling of tumor samples of patients which were diagnosed a secondary GBM and underwent surgery and patients which underwent a second surgery after TMZ treatment due to recurrence of the tumor. We observed substantial activation of the PI3K and MEK/ERK pathways in both groups. However, AKT and CREB phosphorylation was reduced in biopsies of resistant tumors while ERK phosphorylation remained unchanged. Subsequent proteome profiling revealed that multiple RTKs and downstream targets are also activated in three GBM cell lines. We then systematically describe a mechanism of resistance of GBM cell lines and human primary GBM cells to the alkylating drugs TMZ and cisplatin. No specific inhibitor of the upstream RTKs sensitized cells to drug treatment. In contrast, we were able to restore sensitivity to TMZ and cisplatin by inhibiting PI3K in all cell lines and in human primary GBM cells. Interestingly, an opposite effect was observed when we inhibited the MEK/ERK signaling cascade with two different inhibitors. CONCLUSIONS: Temozolomide treatment naive and TMZ resistant GBM biopsies show a distinct activation pattern of the MEK/ERK and PI3K signaling cascades indicating a role of these pathways in resistance development. Both pathways are also activated in GBM cell lines, however, only the PI3K pathway seems to play a crucial role in resistance to alkylating agents and might serve as drug target for chemosensitization.

Impact of aneurysm shape on morbidity after clipping of unruptured intracranial aneurysms.

BACKGROUND: Complex aneurysm shape is a predominant risk factor for aneurysm rupture but its impact on clinical outcome after clipping remains unclear. The objective of the present study was to compare complications and morbidity after clipping of unruptured single-sac aneurysms (SSAs) and aneurysms with multiple sacs (MSAs). METHODS: A retrospective, single-center study was conducted for patients that were treated between 2010 and 2018. We analyzed surgical parameters, treatment-related complications, and morbidity, defined as any increase in the modified Rankin scale at 3-month follow-up. RESULTS: We identified 101 patients (mean age: 52.9 ± 10.5 years) that underwent clipping for 57 SSAs and 44 MSAs. The two groups were comparable regarding aneurysm size and neck width. Clipping of MSAs was associated with a longer operation time (p = 0.008) and increased use of intraoperative indocyanine green (p = 0.016) than SSAs. Complications occurred more often in the MSA group (29.5%) than in the SSA group (14.0%; p = 0.057). Morbidity was significantly higher in the MSA group (20.5%) than in the SSA group (3.5%, p = 0.009). In the univariate analysis, the odds of morbidity were 7.1 times greater for MSAs than for SSAs (95% CI 1.4-34.7). CONCLUSIONS: Morbidity after microsurgical clipping is significantly increased in MSAs as compared to SSAs. This may be attributed to a more difficult clip placement with stronger manipulation of the aneurysm dome and the surrounding brain tissue.

Epineurial Nerve Coaptation: A Biological Nonliving Training Model Using Gradually Thawed Cryopreserved Sciatic Nerves.

The authors present a novel biological nonliving epineurial nerve coaptation training model, which allows cost-efficient practicing on organic mammal nerves and offers an objective performance control on the basis of successful suturing and respecting the 3R model.Anatomic dissection of 40 rat cadavers was performed. Four residents without prior microneurosurgical experience were included. Each trainee performed 20 epineurial nerve coaptations. The number of successful sutures served as qualitative variable and operation time as a quantitative variable for efficiency control.The rate for successful sutures was 51.9% in the first half of trials and improved to 94.4% in the second half. Whereas, the trainees needed a mean time of 34 minutes for the first 10 coaptations, the last 10 coaptations were performed within 24.5 minutes.The authors' presented model is an easily accessible, low-cost microneurosurgical simulation model, allowing a realistic and instructive performance of epineurial nerve coaptation. Because cadaveric nerves are used, an approval of the local ethics committee is not needed. Furthermore, anatomic knowledge about the topography related to the harvest of the sciatic nerve of rats is provided in this study.

Thioredoxin Confers Intrinsic Resistance to Cytostatic Drugs in Human Glioma Cells.

Thioredoxin (Trx) overexpression is known to be a cause of chemotherapy resistance in various tumor entities. However, Trx effects on resistance are complex and depend strictly on tissue type. In the present study, we analyzed the impact of the Trx system on intrinsic chemoresistance of human glioblastoma multiforme (GBM) cells to cytostatic drugs. Resistance of GBM cell lines and primary cells to drugs and signaling inhibitors was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Impact of Trx inhibition on apoptosis was investigated by proteome profiling of a subset of proteins and annexin V apoptosis assays. Trx-interacting protein (TXNIP) was overexpressed by transfection and protein expression was determined by immunoblotting. Pharmacological inhibition of Trx by 1-methyl-2-imidazolyl-disulfide (PX-12) reduced viability of three GBM cell lines, induced expression of active caspase-3, and reduced phosphorylation of AKT-kinase and expression of ß-catenin. Sensitivity to cisplatin could be restored by both PX-12 and recombinant expression of the upstream Trx inhibitor TXNIP, respectively. In addition, PX-12 also sensitized primary human GBM cells to temozolomide. Combined inhibition of Trx and the phosphatidylinositide 3-kinase (PI3K) pathway resulted in massive cell death. We conclude that the Trx system and the PI3K pathway act as a sequential cascade and could potentially present a new drug target.

Interdisciplinary Treatment of Intracranial Infectious Aneurysms.

OBJECTIVE: Intracranial infectious aneurysms (IIAs) are a rare clinical entity without a definitive treatment guideline. In this study, we evaluate the treatment options of these lesions based on our own clinical experience and review the current knowledge of therapy as portrayed in the literature. METHODS: We conducted a single-center retrospective analysis of all patients with an IIA and performed a systematic review of the literature using the MEDLINE database. We undertook a comprehensive literature search using the OVID gateway of the MEDLINE database (1950-October 2015) using the following keywords (in combination): 'infectious', 'mycotic', 'cerebral aneurysm', 'intracranial aneurysm'. 1,721 potentially relevant abstracts were identified and 63 studies were selected for full review. The studies were analysed regarding ruptured versus unruptured aneurysms, aneurysm localization and treatment, as well as clinical and radiological outcome. RESULTS: Our institutional series consisted of 6 patients (median age 57 [32-76]) treated between 2011 and 2015. All patients presented with ruptured IIAs located on the middle cerebral artery (MCA, 5 patients) and anterior cerebral artery (ACA, 1 patient). Five patients were treated by clipping and resecting the aneurysm, 1 patient underwent coiling. All patients received antibiotic therapy and 1 patient died. We further identified 814 patients (median age 35.5 [0-81]) in 63 studies. Locations of the aneurysms were mentioned in 55 studies. The most frequent locations of the aneurysms were: MCA (63.5%), posterior cerebral artery (14%), ACA (9.0%) and others (13.5%). Treatment for IIAs was described in 62 studies: antibiotic treatment (56.1%), a combination of antibiotics and surgery (20.9%) or antibiotics and endovascular treatment (23.0%). Outcome was mentioned in 82.4% of the patients with a mortality rate of 16.8%. An evaluation of treatment outcome was limited due to the heterogeneity of patients in the published case series. CONCLUSION: Antibiotic therapy of patients with IIA is mandatory. However, due to the complexity of the disease and its accompanying comorbidities, a general treatment algorithm could not be defined. Analogous to non-mycotic aneurysms, further treatment decisions require an interdisciplinary approach involving neurosurgeons, interventionists and infectious disease specialists.

Identification of a novel MET mutation in high-grade glioma resulting in an auto-active intracellular protein.

MET has gained interest as a therapeutic target for a number of malignancies because of its involvement in tumorigenesis, invasion and metastasis. At present, a number of inhibitors, both antibodies against MET or its ligand hepatocyte growth factor, and small molecule MET tyrosine kinase inhibitors are in clinical trials. We here describe a novel variant of MET that is expressed in 6% of high-grade gliomas. Characterization of this mutation in a glioma cell line revealed that it consists of an intronic deletion, resulting in a splice event connecting an intact splice donor site in exon 6 with the next splice acceptor site being that of exon 9. The encoded protein lacks parts of the extracellular IPT domains 1 and 2, encoded by exons 7 and 8, resulting in a novel pseudo-IPT and is named MET(Δ7-8). MET(Δ7-8) is located predominantly in the cytosol and is constitutively active. The auto-activating nature of MET(Δ7-8), in combination with a lack of transmembrane localization, renders MET(Δ7-8) not targetable using antibodies, although the protein is efficiently deactivated by MET-specific tyrosine kinase inhibitors. Testing of MET-expressing tumors for the presence of this variant may be important for treatment decision making.

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.

Higher YAP1 Levels Are Associated With Shorter Survival of Patients With Low Grade Astrocytoma.

BACKGROUND/AIM: Glioblastoma multiforme (GBM) is one of the most lethal types of brain cancer with a median survival of only 12 months due to its aggressiveness and lack of effective treatment options. Astrocytomas and oligodendrogliomas are classified as low-grade gliomas (LGG) and have the potential to progress into secondary GBM. YAP1 and TAZ are transcriptional co-activators of the hippo pathway and play an important role in tumorigenesis by controlling cell proliferation and differentiation. The aim of this study was to analyze whether YAP1 and TAZ influence the survival in patients with astrocytoma and oligodendroglioma. PATIENTS AND METHODS: A total of 22 patient samples of astrocytoma and 11 samples of oligodendroglioma were analyzed using real-time PCR. We utilized open-access data from The Cancer Genome Atlas (TCGA) focusing on "brain lower grade glioma". mRNA expression rates were used to validate our findings on survival analysis. RESULTS: Expression of YAP1 was twice as high in astrocytoma than in oligodendroglioma, whereas there was no difference in TAZ. In oligodendrogliomas, the expression of TAZ was higher in relapsed than in primary tumors. Patients with astrocytoma having a high YAP1 expression had a significantly shorter overall survival than patients with lower expression (median survival 161 vs. 86 months, p=0.0248). These findings were validated with survival analysis of TCGA data. CONCLUSION: High YAP1 expression shows a high correlation with poorer overall survival in LGG. YAP1 has higher levels of expression in astrocytomas than in oligodendrogliomas.

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.

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.

Feasibility, Safety, and Efficacy of Endovascular vs. Surgical Treatment of Unruptured Multi-Sac Intracranial Aneurysms in a Single-Center Retrospective Series.

PURPOSE: Multi-sac aneurysms (MSAs) are not uncommon, but studies on their management are scarce. This study aims to evaluate and compare the feasibility, safety, and efficacy of MSAs treated with either clipping or coiling after interdisciplinary case discussion at our center. MATERIALS AND METHODS: We retrospectively analyzed MSAs treated by microsurgical clipping, coiling, or stent-assisted coiling (SAC). Treatment modalities, complications, angiographic results, and clinical outcomes were evaluated. Major neurological events were defined as a safety endpoint and complete occlusion as an efficacy endpoint. RESULTS: Ninety patients (mean age, 53.2±11.0 years; 73 [81.1%] females) with MSAs met our inclusion criteria (clipping, 50; coiling, 19; SAC, 21). Most aneurysms were located in the middle cerebral artery (48.9%). All clipping procedures were technically successful, but endovascular treatment failed in 1 coiling case, and a switch from coiling to SAC was required in 2 cases. The major event rates were 4.0% after clipping (1 major stroke and 1 intracranial hemorrhage) and 0% after endovascular therapy (P=0.667). At mid-term angiographic follow-up (mean 12.0±8.9 months), all 37 followed clipped aneurysms were completely occluded, compared to 8/17 (41.7%) after coiling and 11/15 (73.3%) after SAC (P<0.001). Coiling was significantly associated with incomplete occlusion in the adjusted analysis (odds ratio, 11.7; 95% confidence interval, 2.7-52.6; P=0.001). CONCLUSION: Both endovascular and surgical treatment were feasible and safe for MSAs. As coiling was associated with comparatively high recanalization rates, endovascular treatment may be preferred with stent support.

A novel strategy for intrastriatal dopaminergic cell transplantation: sequential "nest" grafting influences survival and behavioral recovery in a rat model of Parkinson's disease.

Neural transplantation in experimental parkinsonism (PD) is limited by poor survival of grafted embryonic dopaminergic (DA) cells. In this proof-of-principle study we hypothesized that a first regular initial graft may create a "dopaminergic" environment similar to the perinatal substantia nigra and consequently stimulate a subsequent graft. Therefore, we grafted ventral mesencephalic neurons sequentially at different time intervals into the same target localization. Rats with a unilateral lesion of the dopamine neurons produced by injections of 6-hydroxydopamine (6-OHDA) received E14 ventral mesencephalon derived grafts into the DA-depleted striatum. In the control group we grafted all 6 deposits on the first day (d0). The other 4 groups received four graft deposits distributed over 2 implantation tracts followed by a second engraftment injected into the same site 3, 6, 14 and 21 days later. Quantitative assessment of the survival of tyrosine hydroxylase-immunoreactive neurons and graft volume revealed best results for those DA grafts implanted 6 days after the first one. In the present study, a model of short-interval sequential transplantation into the same target-site, so called "nest" grafts were established in the 6-OHDA rat model of PD which might become a useful tool to further elucidate the close neurotrophic and neurotopic interactions between the immediate graft vicinity and the cell suspension graft. In addition, we could show that the optimal milieu was established around the sixth day after the initial transplantation. This may also help to further optimize current transplantation strategies to restore the DA system in patients with PD.

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.

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.