Stephan A. Munich

Dendritic cell exosomes directly kill tumor cells and activate natural killer cells via TNF superfamily ligands

Autocrine and paracrine cell communication can be conveyed by multiple mediators, including membrane-associate proteins, secreted proteins and exosomes. Exosomes are 30–100 nm endosome-derived vesicles consisting in cytosolic material surrounded by a lipid bilayer containing transmembrane proteins. We have previously shown that dendritic cells (DCs) express on their surface multiple TNF superfamily ligands (TNFSFLs), by which they can induce the apoptotic demise of tumor cells as well as the activation of natural killer (NK) cells. In the present study, we demonstrate that, similar to DCs, DC-derived exosomes (DCex) express on their surface TNF, FasL and TRAIL, by which they can trigger caspase activation and apoptosis in tumor cells. We also show that DCex activate NK cells and stimulate them to secrete interferonγ (IFNγ) upon the interaction of DCex TNF with NK-cell TNF receptors. These data demonstrate that DCex can mediate essential innate immune functions that were previously ascribed to DCs.

Thromboembolic complications with Pipeline Embolization Device placement: impact of procedure time, number of stents and pre-procedure P2Y12 reaction unit (PRU) value.

Background Thromboembolic events after Pipeline Embolization Device (PED) placement remain a feared complication among neuroendovascular surgeons. This study aimed to investigate potential risk factors for thromboembolic events in patients undergoing PED placement. Methods Medical records of patients who underwent PED placement from April 2011 to August 2013 were reviewed. Variables including pre-procedure P2Y12 reaction unit (PRU) value, procedure time, number of PEDs deployed and perioperative neurovascular complications were recorded. Multivariate analysis was performed to identify risk factors for perioperative thromboembolic complications. Results Seventy-four patients were identified. Six patients (8.1%) had changes in neurological status after PED placement including five (6.8%) thromboembolic complications and one (1.4%) delayed intracranial hemorrhage; 50.9% of patients had diffusion-weighted imaging (DWI) changes on post-procedural MRI. Longer procedure time (>116 min) and multiple PED placements (>1) were statistically significant risk factors for symptomatic thromboembolic events (p<0.01). A pre-procedural PRU value >208 had an OR of 11.32 (95% CI 0.06 to 212.57) for symptomatic thromboembolic complications, but the result was not statistically significant. Conclusions DWI changes on MRI occurred at a much higher rate than new neurological symptoms following PED placement. Longer procedure time and multiple PED deployment are associated with higher risks of new neurological changes due to thromboembolic events. There was a trend for an increased risk of a symptomatic thromboembolic event in patients with pre-procedural PRU values >208. Reloading (clopidogrel 600 mg) patients with preoperative PRU >208 was safe and may have a protective effect on thromboembolic events.

The Pipeline Embolization Device for the treatment of posterior circulation fusiform aneurysms: lessons learned at a single institution

OBJECT Vertebrobasilar fusiform aneurysms (VFAs) are rare lesions characterized by abnormal dilation and tortuosity of the vertebral and/or basilar arteries. Untreated, these aneurysms have a tendency to progress, often resulting in neurological symptoms or rupture leading to subarachnoid hemorrhage. The microsurgical treatment of these lesions can be difficult due to their location and the circumferential involvement of the arteries. These features make microsurgical treatment prone to high morbidity. The Pipeline Embolization Device (PED) has gained popularity for the treatment of aneurysms of the internal carotid artery. Its use in the posterior circulation has been limited, likely due to a fear of perforating artery occlusion. METHODS The authors retrospectively reviewed their database of patients treated with the PED and identified 12 patients who had VFAs. The clinical features, complications, and outcomes of these patients were analyzed. RESULTS At an average follow-up of 11 months, the mean modified Rankin Scale score was 1.9. Complete aneurysm occlusion was seen in 90% of the patients with radiographic follow-up. Three patients suffered new neurological deficits postoperatively. One of these patients died, while the remaining 2 demonstrated significant clinical improvement at follow-up. CONCLUSIONS With attention to the anatomy of perforating arteries, staged contralateral vertebral artery sacrifice, and adequate platelet inhibition, PED may be an effective treatment option-alone or in a hybrid construct with stents of less coverage for VFAs-with an acceptable complication rate.

Dendritic-cell exosomes cross-present Toll-like receptor-ligands and activate bystander dendritic cells.

Dendritic cells (DCs) are the major sentinel, antigen-presenting and regulatory components of the immune system. One of the central DC functions is to rapidly sense and alert host immune system of a pathogen invasion. In the present study, we investigated the role of DC exosomes (DCex) in this sentinel function. We demonstrated that DCex could bind bacterial Toll-like-receptor ligands (TLR-Ls), and acquire their ability to strongly activate bystander DCs. Consequently, bystander DCs enhance the expression of transmembrane tumor necrosis factor, secretion of proinflammatory cytokines and cross-talk with natural killer cells leading to the elevated secretion of IFNγ. These findings newly show that DCex can bind and cross-present TLR-Ls to innate-immunity effector cells, and indicate a potent mechanism to systemically alert the host immune system of pathogen invasion. They also suggest a potential novel strategy to generate effective vaccines by binding TLR-L-immune adjuvants to DCex.

Stent assisted embolization of 64 anterior communicating artery aneurysms

Introduction Anterior communicating artery (ACoA) aneurysms comprised over half of the ruptured aneurysms in the International Subarachnoid Trial. Endovascular treatment of ACoA aneurysms has provided good results, but until the introduction of intracranial stents, many ACoA aneurysms could not be treated without craniotomy. The current study analyzes the results of ACoA aneurysm treatment using stent assisted embolization. Methods 64 patients with ACoA aneurysms underwent stent assisted aneurysm repair. Four were treated in the acute rupture phase and a fifth ruptured aneurysm was stented in a second procedure after initial coiling. Five aneurysms were 10 mm or more in greatest diameter. Follow-up angiography was performed 6 months after treatment; then, patients were followed with annual MR angiography. Technical, clinical, and long term radiographic results were analyzed. Results Stents were successfully deployed in each case. One patient was eventually treated with a three stent construct and died of perioperative hemorrhage. One major stroke occurred during a separate procedure when a patient was taken off antiplatelet medications. These cases were the only aneurysm related morbidity (1.6%) and mortality (1.6%) events during the entire follow-up period. After stent assisted embolization, 32 (50.0%) ACoA aneurysms were completely occluded, 15 (23.4%) had residual neck, and 17 (26.6%) had residual filling. At first radiographic follow-up, 39 of 55 (70.9%) showed complete occlusion. Three (5.5%) total aneurysms required retreatment. Conclusions Stent assisted aneurysm treatment was a safe and effective option in this series of ACoA aneurysms with maximum diameter less than 15 mm. ACoA aneurysms may be more likely to recur regardless of treatment option, but stent assisted embolization may be durable after stable initial radiographic follow-up.

Complication analysis in nitinol stent-assisted embolization of 486 intracranial aneurysms.

OBJECT Stent-assisted embolization (SAE) has broadened the scope of endovascular cerebral aneurysm treatment. The risks associated with stent selection and configuration are poorly defined. In this study, the authors aimed to characterize the risk factors that contribute to complications in SAE of intracranial aneurysms. METHODS Over a 10-year period, a single surgeon treated 486 aneurysms with SAE in which open-cell Neuroform or closed-cell Enterprise stents were used. Single stents were used in 386 cases, overlapping stents were deployed in 80 cases, and Y-configuration stents were used in the remaining 20 cases. All neurological complications, which included transient deficits, were analyzed; disabling strokes and death were considered major complications. The chi-square test and multivariate logistic regression were used to evaluate the influence of aneurysm size and morphology, aneurysm location, stent selection, and stent configuration on complication rates. RESULTS There were 7 deaths (1.4%), 9 major strokes (1.9%), and 18 minor neurological complications (3.7%). For all complications, multivariate analysis revealed that large aneurysm size (10-25 mm; p = 0.01), giant aneurysm size (> 25 mm; p = 0.04), fusiform aneurysm morphology (p = 0.03), and using a Y-configuration stent (p = 0.048) were independent risk factors. For the major complications, independent risk factors included an aneurysm in the posterior circulation (p = 0.02), using an overlapping stent configuration (p = 0.03), and using a Y-configuration stent (p < 0.01). CONCLUSIONS In this series, SAE for cerebral aneurysm treatment carried an acceptable complication rate. With continued innovations in techniques and devices and with increased experience, the complication rates associated with SAE may be even lower in the future.

Arteriovenous malformation embocure score: AVMES.

Background Cerebral arteriovenous malformations (CAVMs) may be treated with microsurgery, radiosurgery, endovascular surgery, or a combination of these modalities. Grading scales are available to aid the assessment of curative risk for microsurgery and radiosurgery. No grading system has been developed to assess the curative risk of endovascular surgery. Objective To report our retrospective application of the AVM embocure score to patients treated at our institution between 2005 and 2011 Methods We performed a retrospective review of 39 patients with CAVM treated at our institution between 2005 and 2011 with the primary aim of achieving a curative embolization. After reviewing all the different variables associated with the conventional Onyx embolization technique for CAVMs, we identified the following as the most relevant characteristics influencing the chances for complete angiographic embolization and complication risk: the number of arterial pedicles and draining veins, size of AVM nidus, and vascular eloquence. We sought to develop a scoring system to assess the complication risk for a curative embolization of CAVM with liquid embolic Onyx (Covidien, Irvine, California, USA). We developed the AVM embocure score (AVMES). This scoring system ranges from 3 to 10 and is the arithmetic sum of the number of arterial pedicles feeding the AVM (≤3, 4–6, >6), the number of draining veins (≤3, 4–6, >6), the size of the AVM nidus in centimeters (≤3, 4–6, >6), and the vascular eloquence (0–1). We applied AVMES to the same cohort of patients and validated the predictability of complete angiographic embolization and expected clinical risk of complication. Results In lesions with an AVMES of 3 (n=8), there was a 100% rate of complete AVM obliteration and 0% rate of major complications. In AVMES 4 (n=12) lesions, there was 75% complete obliteration rate, with 8% major morbidity. In AVMES 5 (n=9) lesions, there was 78% complete obliteration and 11% major morbidity. In AVMES >5 (n=10) there was 20% complete obliteration and 30% major morbidity. Receiver-operator curve analysis showed that this scoring system was robust in its discriminative ability, with an area under the curve (AUC) of 0.8356 for complete obliteration without complication, AUC=0.8240 for complete obliteration regardless of the presence of major morbidity, and AUC=0.7529 for major morbidity. Conclusions The AVMES complements existing scoring systems for microsurgery and radiosurgery. It provides a valuable tool for risk assessment during the complex decision-making process in treating AVMs that accounts for angioarchitectural features of particular relevance to endovascular surgeons.

Frameless neuronavigation based only on 3D digital subtraction angiography using surface-based facial registration

OBJECT Cerebrovascular lesions can have complicated abnormal anatomy that is not completely characterized by CT or MR angiography. Although 3D rotational angiography provides superior spatial and temporal resolution, catheter angiograms are not easily registered to the patient, limiting the use of these images as a source for neuronavigation. However, 3D digital subtraction angiography (DSA) contains not only vascular anatomy but also facial surface anatomy data. The authors report a novel technique to register 3D DSA images by using only the surface anatomy contained within the data set without having to fuse the DSA image set to other imaging modalities or use fiducial markers. METHODS A cadaver model was first created to assess the accuracy of neuronavigation based on 3D DSA images registered by facial surface anatomy. A 3D DSA scan was obtained of a formalin-fixed cadaver head, with acquisitions of mask and contrast runs. The right common carotid artery was injected prior to the contrast run with a 45% contrast solution diluted with water-soluble red liquid latex. One week later, the head was registered to a neuronavigation system loaded with the 3D DSA images acquired earlier using facial surface anatomy. A right pterional craniotomy was performed and 10 different vascular landmarks were identified and measured for accuracy using the neuronavigation system. Neuronavigation based only on 3D DSA was then used to guide an open clipping procedure for a patient who presented with a ruptured distal lenticulostriate aneurysm. RESULTS The accuracy of the measurements for the cadaver model was 0.71 ± 0.25 mm (mean ± SE), which is superior to the 1.8-5 mm reported for neuronavigation. The 3D DSA-based navigation-assisted surgery for the distal lenticulostriate aneurysm aided in localization, resulting in a small craniotomy and minimal brain dissection. CONCLUSIONS This is the first example of frameless neuronavigation based on 3D catheter angiography registered by only the surface anatomy data contained within the 3D DSA image set. This is an easily applied technique that is beneficial for accurately locating vascular pathological entities and reducing the dissection burden of vascular lesions.

Spontaneous involution of a Rathke's cleft cyst in a patient with normal cortisol secretion.

Background: Rathkes cleft cyst (RCC) is a lesion derived from maldeveloped remnants of a dorsal invagination of the stomodeal ectoderm (Rathkes pouch). Although commonly found on autopsy, these lesions rarely become symptomatic during an individuals lifetime. When symptoms occur, they most often include headaches, visual disturbances, and/or varying degrees of hypopituitarism. The natural history remains unclear. The current standard of care includes surgical drainage and biopsy of the cyst wall or surgical resection of symptomatic lesions; however, debate exists regarding the management of asymptomatic lesions. Rare reports of spontaneously resolving RCC can be found in the literature. Case Description: We describe the management of a case of RCC in an 8½-year-old girl who presented with a history of growth deceleration since 4 years of age and near-growth arrest since 7 years of age. Her parents also described a tendency towards polydipsia since she was 2 years of age. Endocrine evaluation revealed growth hormone deficiency, central hypothyroidism, and diabetes insipidus, but normal cortisol secretion. The patient experienced no symptoms characteristic of intracranial or sellar mass. Neurologic examination was normal; formal ophthalmologic examination revealed no deficits. The magnetic resonance imaging (MRI) was consistent with RCC. The patient was treated medically for her hormone deficiencies. Over the next year, her sellar mass spontaneously involuted. Twenty-seven months after her initial presentation to our clinic, imaging revealed no sellar mass; the patient remained on hormone replacement therapy. Conclusion: Although the natural history of RCC requires further study, observation with serial MRI may be an acceptable management strategy in the absence of debilitating symptoms.

“Contrast-Less” Stent-Assisted Coiling of an A1 Aneurysm

BACKGROUND Iodine-based contrast medium used in diagnostic and therapeutic cerebrovascular imaging may cause renal toxicity, especially in patients with underlying renal impairment. Contrast dilution may impede efforts of the neurointerventionalist to treat intracranial vascular pathology. METHODS A 36-year-old man with renal impairment presented with an unruptured A1 segment anterior cerebral artery aneurysm. Previously obtained magnetic resonance angiography was fused with intraoperative noncontrast computed tomography and live 2-dimensional fluoroscopic images. The aneurysm was successfully treated with stent-assisted coil embolization without the use of contrast. RESULTS Neurointervention without contrast was feasible, and although the presented case is one example, the imaging fusion techniques used in this case can substantially decrease the exposure to contrast and subsequent risk of renal injury during intracranial procedures. CONCLUSIONS Further development of and experience with this technique is needed to improve its safety and efficacy.