A minimally invasive endovascular approach to the cerebellopontine angle cistern enables broad CNS biodistribution of scAAV9-CB-GFP.

Neurological disorders pose a challenge for targeted therapy due to restricted access of therapeutic agents to the central nervous system (CNS). Current methods are limited by procedure-related risks, invasiveness, and insufficient CNS biodistribution. A novel percutaneous transvenous technology, currently in clinical trials for communicating hydrocephalus, offers a minimally invasive approach by providing endovascular access to the cerebrospinal fluid-filled cerebellopontine angle (CPA) cistern. We hypothesized that drug delivery to the CPA cistern could yield widespread CNS distribution. Using an ovine model, we compared the biodistribution of scAAV9-CB-GFP following CPA cistern infusion with previously reported cisterna magna (CM) administration. Targeting both the CPA cistern and CM in sheep, we employed a lumbar spine-inserted microcatheter under fluoroscopy. CPA delivery of AAV9 demonstrated biodistribution and transduction in the cerebral cortices, striatum, thalamus, midbrain, cerebellum, and spinal cord, with minor liver distribution comparable to CM. The favorable safety profile in humans with hydrocephalus suggests that percutaneous endovascular injection into the CPA could offer a clinically safer and minimally invasive delivery system for CNS gene and cell-based therapies.

Inferior Ophthalmic Vein-Dominant Dural Cavernous Fistula Embolization via Combined Orbitotomy and Direct Puncture of Inferior Ophthalmic Vein: A Case Report and Literature Review.

Dural carotid-cavernous fistulas (DCF) typically drain into the superior ophthalmic vein. Predominant involvement of the inferior ophthalmic vein (IOV) is rare, with only 4 documented cases in the literature. Here, the authors describe a case of a 51-year-old man who presented with acute left-sided proptosis, dysmotility, and vision loss and was found to have an IOV-dominant type D dural carotid-cavernous fistulas. The fistula could not be embolized by transfemoral endovascular access or orbitotomy alone and was ultimately managed with combined orbitotomy and direct IOV puncture. All previous reports of IOV-dominant dural carotid-cavernous fistulas in the literature were similarly inaccessible via the transfemoral approach. This case highlights the challenges of IOV cutdown and proposes an alternative management strategy. When IOV cutdown is precluded by the fragile, collapsed, or deep nature of the vessel, conversion to percutaneous IOV puncture may offer a safe and effective approach and mitigate the risks of direct puncture alone.

Prospective study on embolization of intracranial aneurysms with the pipeline device (PREMIER study): 3-year results with the application of a flow diverter specific occlusion classification.

BACKGROUND: The pipeline embolization device (PED; Medtronic) has presented as a safe and efficacious treatment for small- and medium-sized intracranial aneurysms. Independently adjudicated long-term results of the device in treating these lesions are still indeterminate. We present 3-year results, with additional application of a flow diverter specific occlusion scale. METHODS: PREMIER (prospective study on embolization of intracranial aneurysms with pipeline embolization device) is a prospective, single-arm trial. Inclusion criteria were patients with unruptured wide-necked intracranial aneurysms ≤12 mm. Primary effectiveness (complete aneurysm occlusion) and safety (major neurologic event) endpoints were independently monitored and adjudicated. RESULTS: As per the protocol, of 141 patients treated with a PED, 25 (17.7%) required angiographic follow-up after the first year due to incomplete aneurysm occlusion. According to the Core Radiology Laboratory review, three (12%) of these patients progressed to complete occlusion, with an overall rate of complete aneurysm occlusion at 3 years of 83.3% (115/138). Further angiographic evaluation using the modified Cekirge-Saatci classification demonstrated that complete occlusion, neck residual, or aneurysm size reduction occurred in 97.1%. The overall combined safety endpoint at 3 years was 2.8% (4/141), with only one non-debilitating major event occurring after the first year. There was one case of aneurysm recurrence but no cases of delayed rupture in this series. CONCLUSIONS: The PED device presents as a safe and effective modality in treating small- and medium-sized intracranial aneurysms. The application of a flow diverter specific occlusion classification attested the long-term durability with higher rate of successful aneurysm occlusion and no documented aneurysm rupture. TRIAL REGISTRATION: NCT02186561.

First-in-human endovascular treatment of hydrocephalus with a miniature biomimetic transdural shunt.

Surgical ventriculoperitoneal shunting remains standard treatment for communicating hydrocephalus, despite persistently elevated infection and revision rates. A novel minimally invasive endovascular cerebrospinal fluid (CSF) shunt was developed to mimic the function of the arachnoid granulation which passively filters CSF from the central nervous system back into the intracranial venous sinus network. The endovascular shunt is deployed via a femoral transvenous approach across the dura mater into the cerebellopontine angle cistern. An octogenarian with intractable hydrocephalus following subarachnoid hemorrhage underwent successful endovascular shunting, resulting in swift intracranial pressure reduction from 38 to <20 cmH2O (<90 min) and resolution of ventriculomegaly. This first successful development of a percutaneous transluminal venous access to the central nervous system offers a new pathway for non-invasive treatment of hydrocephalus and the potential for intervention against neurological disorders.

Pivotal trial of the Neuroform Atlas stent for treatment of posterior circulation aneurysms: one-year outcomes.

BACKGROUND: Stent-assisted coiling of wide-necked intracranial aneurysms (IAs) using the Neuroform Atlas Stent System (Atlas) has shown promising results. OBJECTIVE: To present the primary efficacy and safety results of the ATLAS Investigational Device Exemption (IDE) trial in a cohort of patients with posterior circulation IAs. METHODS: The ATLAS trial is a prospective, multicenter, single-arm, open-label study of unruptured, wide-necked, IAs treated with the Atlas stent and adjunctive coiling. This study reports the results of patients with posterior circulation IAs. The primary efficacy endpoint was complete aneurysm occlusion (Raymond-Roy (RR) class I) on 12-month angiography, in the absence of re-treatment or parent artery stenosis >50%. The primary safety endpoint was any major ipsilateral stroke or neurological death within 12 months. Adjudication of the primary endpoints was performed by an imaging core laboratory and a Clinical Events Committee. RESULTS: The ATLAS trial enrolled and treated 116 patients at 25 medical centers with unruptured, wide-necked, posterior circulation IAs (mean age 60.2±10.5 years, 81.0% (94/116) female). Stents were placed in all patients with 100% technical success rate. A total of 95/116 (81.9%) patients had complete angiographic follow-up at 12 months, of whom 81 (85.3%) had complete aneurysm occlusion (RR class I). The primary effectiveness outcome was achieved in 76.7% (95% CI 67.0% to 86.5%) of patients. Overall, major ipsilateral stroke and secondary persistent neurological deficit occurred in 4.3% (5/116) and 1.7% (2/116) of patients, respectively. CONCLUSIONS: In the ATLAS IDE posterior circulation cohort, the Neuroform Atlas Stent System with adjunctive coiling demonstrated high rates of technical and safety performance. Trial registration number https://clinicaltrials.gov/ct2/show/NCT02340585.

Neuroform Atlas Stent for Treatment of Middle Cerebral Artery Aneurysms: 1-Year Outcomes From Neuroform Atlas Stent Pivotal Trial.

BACKGROUND: Heterogeneous effect of endovascular aneurysm therapy has been observed across different anatomic locations. There is a paucity of data for stent-assisted coiling of middle cerebral artery (MCA) aneurysms. OBJECTIVE: To present the results of the MCA aneurysm group from the Neuroform Atlas (Stryker Neurovascular) investigational device exemption (IDE) trial. METHODS: The Atlas IDE trial is a prospective, multicenter, single-arm, open-label study of wide-neck aneurysms (neck ≥ 4 mm or dome-to-neck ratio < 2) in the anterior circulation treated with the Neuroform Atlas Stent and approved coils. Follow-up was obtained immediately postprocedure and 2, 6, and 12 mo postoperatively. We herein describe safety and efficacy outcomes, and functional independence of the subjects with aneurysms from all segments of MCA. RESULTS: A total of 35 patients were included (27 MCA bifurcation, 5 M1, 3 M2). The mean aneurysm size was 6.0 ± 1.8 mm, and the mean neck was 4.4 ± 1.2 mm. Technical procedural success was achieved in all patients. A total of 26 patients had follow-up digital subtraction angiography available at 12 mo, with 80.8% (21/26) having complete aneurysm occlusion. Twelve-month safety data were collected for 91.4% (32/35), 8.5% (3/35) had primary safety endpoint, all 3 major ischemic strokes. Mortality occurred in 2 patients beyond 30 d unrelated to procedure (1 gallbladder cancer and 1 fentanyl intoxication). At 1 yr, modified Rankin Score was 0 to 2 in 84.4% (27/32), 3 in 9.4%, and 3 patients were missing. Approximately 5.7% (2/35) of patients were retreated at 12 mo. CONCLUSION: Stent-assisted coiling with the Neuroform Atlas Stent is a viable alternative to clipping for selected MCA aneurysms. Complete aneurysm occlusion rates have improved compared to historical data. Proper case selection can lead to acceptable endovascular results.

Performance of Radiomics derived morphological features for prediction of aneurysm rupture status.

BACKGROUND: Morphological differences between ruptured and unruptured cerebral aneurysms represent a focus of neuroimaging researchfor understanding the mechanisms of aneurysmal rupture. We evaluated the performance of Radiomics derived morphological features, recently proposed for rupture status classification, against automatically measured shape and size features previously established in the literature. METHODS: 353 aneurysms (123 ruptured) from three-dimensional rotational catheter angiography (3DRA) datasets were analyzed. Based on a literature review, 13 Radiomics and 13 established morphological descriptors were automatically extracted per aneurysm, and evaluated for rupture status prediction using univariate and multivariate statistical analysis, yielding an area under the curve (AUC) metric of the receiver operating characteristic. RESULTS: Validation of overlapping descriptors for size/volume using both methods were highly correlated (p<0.0001, R 2=0.99). Univariate analysis selected AspectRatio (p<0.0001, AUC=0.75), Non-sphericity Index (p<0.0001, AUC=0.75), Height/Width (p<0.0001, AUC=0.73), and SizeRatio (p<0.0001, AUC=0.73) as best among established descriptors, and Elongation (p<0.0001, AUC=0.71) and Flatness (p<0.0001, AUC=0.72) among Radiomics features. Radiomics Elongation correlated best with established Height/Width (R 2=0.52), whereas Radiomics Flatness correlated best with Ellipticity Index (R 2=0.54). Radiomics Sphericity correlated best with Undulation Index (R 2=0.65). Best Radiomics performers, Elongation and Flatness, were highly correlated descriptors (p<0.0001, R 2=0.75). In multivariate analysis, established descriptors (Height/Width, SizeRatio, Ellipticity Index; AUC=0.79) outperformed Radiomics features (Elongation, Maximum3Ddiameter; AUC=0.75). CONCLUSION: Although recently introduced Radiomics analysis for aneurysm shape and size evaluation has the advantage of being an efficient operator independent methodology, it currently offers inferior rupture status discriminant performance compared with established descriptors. Future research is needed to extend the current Radiomics feature set to better capture aneurysm shape information.

Increased focal internal carotid artery angulation in patients with posterior communicating artery aneurysms.

BACKGROUND: Aneurysms at the posterior communicating artery (PCOM) origin represent the most common location on the internal carotid artery (ICA), and are associated with greater recurrence following endovascular treatment. We evaluate the association between ICA angulation in three-dimensional (3D) space and PCOM aneurysmal development, using high-resolution 3D rotational angiography (3DRA) studies. METHODS: 3DRA datasets were evaluated in 70 patients with PCOM aneurysms, 31 non-aneurysmal contralateral, and 86 healthy controls (187 total). The local angle formed by upstream and downstream ICA segments at the PCOM origin, αICA@PCOM, was measured using 3DRA multiplanar reconstruction. Computational fluid dynamics (CFD) analysis was performed on parametric and patient-based models. RESULTS: αICA@PCOM was significantly larger in aneurysm-bearing ICA segments (68.14±11.91°) compared with non-aneurysmal contralateral (57.17±10.76°, p<0.001) and healthy controls (48.13±13.68°, p<0.001). A discriminant threshold αICA@PCOM value of 61° (87% specificity, 80% sensitivity) was established (area under the curve (AUC)=0.88). Ruptured PCOM aneurysms had a significantly larger αICA@PCOM compared to unruptured (72.65±15.16° vs 66.35±9.94°, p=0.04). In parametric and patient-based CFD analysis, a large αICA@PCOM induces high focal pressure at the PCOM origin, relatively low wall shear stress (WSS), and high proximal WSS spatial gradients (WSSG). CONCLUSION: ICA angulation at PCOM origin is significantly higher in vessels harboring PCOM aneurysms compared with contralateral and healthy ICAs. This sharper bend in the ICA leads to high focal pressure at the aneurysm neck, low focal WSS and high proximal WSSG. These findings underline the importance of morphological ICA variations and the likelihood of PCOM aneurysm, an association which can inform clinical decisions and may serve in predictive analytics.

Prospective study on embolization of intracranial aneurysms with the pipeline device: the PREMIER study 1 year results.

BACKGROUND: Preliminary clinical studies on the safety and efficacy of the pipeline embolization device (PED) for the treatment of small/medium aneurysms have demonstrated high occlusion rates with low complications. OBJECTIVE: To evaluate the safety and effectiveness of the PED for treatment of wide necked small and medium intracranial aneurysms. METHODS: PREMIER is a prospective, multicenter, single arm trial. Patients were treated with the PED for unruptured wide necked aneurysms, measuring ≤12 mm along the internal carotid artery or vertebral artery, between July 2014 and November 2015. At 1 year post-procedure, the primary effectiveness endpoint was complete occlusion (Raymond grade 1) without major parent vessel stenosis (≤50%) or retreatment, and the primary safety endpoint was major stroke in the territory supplied by the treated artery or neurologic death. RESULTS: A total of 141 patients were treated with PEDs (mean age 54.6±11.3 years, 87.9% (124/141) women). Mean aneurysm size was 5.0±1.92 mm, and 84.4% (119/141) measured <7 mm. PED placement was successful in 99.3% (140/141) of patients. Mean number of PEDs implanted per patient was 1.1±0.26; a single PED was used in 92.9% (131/141) of patients. At 1 year, 97.9% (138/141) of patients underwent follow-up angiography with 76.8% (106/138) of patients having met the study's primary effectiveness endpoint. The combined major morbidity and mortality rate was 2.1% (3/140). CONCLUSIONS: Treatment of wide necked small/medium aneurysms with the PED results in high rates of complete occlusion without significant parent vessel stenosis and low rates of permanent neurologic complications. TRIAL REGISTRATION: NCT02186561.

Genome Sequence of a Facklamia hominis Isolate from a Patient with Urosepsis.

The genome sequence of a Facklamia hominis strain isolated from the urine of a patient with acute cystitis and sepsis is reported. The genome contains ermB and tet(M) genes, consistent with the isolate's phenotypic resistance to macrolides and tetracycline.

Neuroform Atlas Stent System for the treatment of intracranial aneurysm: primary results of the Atlas Humanitarian Device Exemption cohort.

BACKGROUND AND OBJECTIVE: Stent-assisted coil embolization is a well-established treatment of intracranial wide-necked aneurysms. The Neuroform Atlas Stent System is a new generation microstent designed to enhance coil support, conformability, deliverability, and improve deployment accuracy. We present the 1-year efficacy and angiographic results of the Humanitarian Device Exemption (HDE) cohort from the Atlas Investigational Device Exemption (IDE) clinical trial. METHOD: The Atlas IDE trial is a prospective, multicenter, single-arm, open-label study of unruptured wide-necked intracranial aneurysms treated with the Neuroform Atlas stent and approved coils. The primary efficacy endpoint was the rate of 12-month complete aneurysm angiographic occlusion (Raymond class I) without target aneurysm retreatment or significant parent artery stenosis (>50%) at the target location. The primary safety endpoint was the rate of major ipsilateral stroke or neurological death within 12 months. Imaging core laboratory and Clinical EventsCommittee adjudicated the primary endpoints. RESULTS: 30 patients were enrolled at eight US centers, with 27 patients completing the 12-month angiographic follow-up. The mean age was 59.4±11.8 years and 24/30 patients (80%) were women. The mean aneurysm size was 5.3±1.7 mm and the dome:neck ratio was 1.1±0.2. Procedural technical success of Neuroform Atlas Stent deployment was 100%. 27 patients completed 12-month angiographic follow-up and 30 patients completed their 6-month follow-up. When applying the last observation carried forward method, the primary efficacy endpoint was observed in 26/30 patients (86.7%, 95% CI 69.3% to 96.2%) compared with 25/27 patients (92.6%, 95% CI 75.7% to 99.1%) who completed the 12-month angiographic follow-up. The primary safety endpoint of stroke occurred in one patient (3.3%), who made a complete clinical recovery at discharge. There were no neurological deaths. CONCLUSION: The Neuroform Atlas stent in conjunction with coils demonstrated a high rate of complete aneurysm occlusion at 12-month angiographic follow-up, with an improved safety profile in the HDE cohort. CLINICAL TRIALGOV REGISTRATION NUMBER: NCT0234058;Results.

Anatomical characterization of the inferior petrosal sinus and adjacent cerebellopontine angle cistern for development of an endovascular transdural cerebrospinal fluid shunt.

BACKGROUND AND PURPOSE: We evaluated the inferior petrosal sinus (IPS) and adjacent cerebellopontine angle (CPA) cistern as a potential implantation site for a novel venous endovascular transdural CSF shunt concept to treat communicating hydrocephalus. We analyzed the dimensions of the IPS, CPA cistern, and distances to adjacent neurovascular structures. MATERIALS AND METHODS: Gadolinium enhanced T1 weighted brain MRI datasets of 36 randomly selected patients, aged 20-80 years, were analyzed with three-dimensional multiplanar reconstruction to measure IPS diameter and length, CPA cistern depth, and IPS proximity to the vertebrobasilar arteries and brainstem. Statistical analysis was used to assess gender, sidedness, and age dependence. RESULTS: Mean IPS diameter ranged from 2.27 mm to 3.31 mm at three axial levels, with >90% larger than 1.46 mm. CPA cistern adjacent to the IPS exhibited a mean depth of 3.86 mm to 7.39 mm between the dura and brainstem at corresponding axial levels. There was no side dependence except for a longer distance from the IPS to the basilar artery on the left compared with the right (9.72 vs 7.28, P<0.019). Linear regression analysis showed that the distance from the IPS to the brainstem was statistically significantly increased with age (P<0.0002) and was greater in men, with little side variation (P=0.524). CONCLUSION: Our results demonstrate sufficient CSF CPA cisternal space adjacent to the IPS and support the feasibility of an endovascular catheter delivered transdural implantable shunt. Such a device could serve to mimic the function of the arachnoid granulation by establishing a regulated path for CSF flow from the intracranial subarachnoid space to the venous system and provide a treatment for communicating hydrocephalus.

Critical role of angiographic acquisition modality and reconstruction on morphometric and haemodynamic analysis of intracranial aneurysms.

BACKGROUND: Subtracted 3-D rotational angiography (3DRA) and cone-beam computed tomography angiography (CBCT-A) are often used in assessing cerebral aneurysm shape and haemodynamic profile. We sought to evaluate the effect of imaging modality, reconstruction parameters, and kernel selection on patient-derived aneurysm morphology and computational fluid dynamic (CFD) analysis to assess its potential contribution to inter-study variability. METHODS: Four patients (five aneurysms) underwent concurrent 3DRA followed by high-resolution CBCT-A. Six models were reconstructed per aneurysm: 3DRA reconstructed with 0.28 and 0.14 mm voxel sizes (large and small volume of interest (VOI) respectively), and two kernel types (normal/smooth). CBCT-A was reconstructed over small VOI using normal/sharp kernel. Maximal dome dimension, neck diameter and dome/neck ratio were evaluated in 3D. Wall shear stress (WSS) magnitude was evaluated on the entire aneurysm dome and in the 5% dome areas covered by lowest (LWSS) and highest (HWSS) WSS. Parameters were evaluated with pairwise t-test analysis. RESULTS: Smaller VOI reconstructions resulted in smaller Dmax (P value=0.03) and Dmax/neck (P value=0.006) and in larger LWSS (P value=0.03). Use of sharp kernel led to narrower neck (P value=0.04) and higher Dmax/neck values (P value=0.02). CBCT-A resulted in statistically different aneurysm shape (up to 24% difference) and haemodynamics (up to 97% difference) compared with 3DRA. CONCLUSION: The choice of catheter 3D angiographic modality and reconstruction kernel has a critical impact on derived aneurysm morphological and haemodynamic analysis. The resultant variability can confound and obscure underlying differences within patient populations and between studies performed at different centres using divergent techniques, compromising the accuracy of quantitative aneurysm analysis.

CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection.

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4(+) T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4(+) T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8(+) memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

Vascular complications in autosomal dominant polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease. Relentless cyst growth substantially enlarges both kidneys and culminates in renal failure. Patients with ADPKD also have vascular abnormalities; intracranial aneurysms (IAs) are found in ∼10% of asymptomatic patients during screening and in up to 25% of those with a family history of IA or subarachnoid haemorrhage. As the genes responsible for ADPKD­PKD1 and PKD2­have complex integrative roles in mechanotransduction and intracellular calcium signalling, the molecular basis of IA formation might involve focal haemodynamic conditions exacerbated by hypertension and altered flow sensing. IA rupture results in substantial mortality, morbidity and poor long-term outcomes. In this Review, we focus mainly on strategies for screening, diagnosis and treatment of IAs in patients with ADPKD. Other vascular aneurysms and anomalies­including aneurysms of the aorta and coronary arteries, cervicocephalic and thoracic aortic dissections, aortic root dilatation and cerebral dolichoectasia­are less common in this population, and the available data are insufficient to recommend screening strategies. Treatment decisions should be made with expert consultation and be based on a risk-benefit analysis that takes into account aneurysm location and morphology as well as patient age and comorbidities.

IL-15 induces strong but short-lived tumor-infiltrating CD8 T cell responses through the regulation of Tim-3 in breast cancer.

IL-15 has pivotal roles in the control of CD8(+) memory T cells and has been investigated as a therapeutic option in cancer therapy. Although IL-15 and IL-2 share many functions together, including the stimulation of CD8 T cell proliferation and IFN-γ production, the different in vivo roles of IL-15 and IL-2 have been increasingly recognized. Here, we explored the different effects of IL-15 and IL-2 on tumor-infiltrating (TI) T cells from resected breast tumors. We found that neither IL-2 nor IL-15 induced intratumoral CD8 T cell proliferation by itself, but after CD3/CD28-stimulation, IL-15 induced significantly higher proliferation than IL-2 during early time points, at day 2, day 3 and day 6. However, the IL-15-induced proliferation leveled off at day 9 and day 12, whereas IL-2 induced lower but progressive proliferation at each time point. Furthermore, IL-15 caused an early and robust increase of IFN-γ in the supernatant of TI cell cultures, which diminished at later time points, while the IL-2-induced IFN-γ production remained constant over time. In addition, the IL-15-costimulated CD8 T cells presented higher frequencies of apoptotic cells. The diminishing IL-15-induced response was possibly due to regulatory and/or exhaustion mechanisms. We did not observe increased IL-10 or PD-1 upregulation, but we have found an increase of Tim-3 upregulation on IL-15-, but not IL-2-stimulated cells. Blocking Tim-3 function using anti-Tim-3 antibodies resulted in increased IL-15-induced proliferation and IFN-γ production for a prolonged period of time, whereas adding Tim-3 ligand galectin 9 led to reduced proliferation and IFN-γ production. Our results suggest that IL-15 in combination of Tim-3 blocking antibodies could potentially act as an IL-2 alternative in tumor CD8 T cell expansion in vitro, a crucial step in adoptive T cell therapy.

Enterprise stenting for intracranial aneurysm treatment induces dynamic and reversible age-dependent stenosis in cerebral arteries.

BACKGROUND: Although intracranial stenting has been associated with in-stent stenosis, the vascular response of cerebral vessels to the deployment of the Enterprise vascular reconstruction device is poorly defined. OBJECTIVE: To evaluate the change in parent vessel caliber that ensues after Enterprise stent placement. METHODS: Seventy-seven patients with 88 aneurysms were treated using Enterprise stent-assisted coil embolization and underwent high-resolution three-dimensional rotational angiography followed by three-dimensional edge-detection filtering to remove windowing-dependence measurement artifact. Orthogonal diameters and cross-sectional areas (CSAs) were measured proximal and distal on either side of the leading stent edge (points A, B), trailing stent edge (points D, E), and at mid-stent (point C). RESULTS: Enterprise stent deployment caused an instant increase in the parent artery CSA by 8.98% at D, which was followed 4-6 months later by significant in-stent stenosis (15.78% at A, 27.24% at B, 10.68% at C, 32.12% at D, and 28.28% at E) in the stented artery. This time-dependent phenomenon showed resolution which was complete by 12-24 months after treatment. This target vessel stenosis showed significant age dependence with greater response in the young. No flow-limiting stenosis requiring treatment was observed in this series. CONCLUSIONS: Use of the Enterprise stent is associated with a significant dynamic and spontaneously resolvable age-dependent in-stent stenosis. Further study is warranted on the clinical impact, if any, of this occurrence.

Use of cone-beam computed tomography angiography in planning for gamma knife radiosurgery for arteriovenous malformations: a case series and early report.

BACKGROUND: The effectiveness of Gamma Knife radiosurgery (GKR) for cerebral arteriovenous malformations (AVMs) is predicated on inclusion of the entire nidus while excluding normal tissue. As such, GKR may be limited by the resolution and accuracy of the imaging modality used in targeting. OBJECTIVE: We present the first case series to demonstrate the feasibility of using ultrahigh-resolution C-arm cone-beam computed tomography angiography (CBCT-A) in AVM targeting. METHODS: From June 2009 to June 2013, CBCT-A was used for targeting of all patients with AVMs treated with GKR at our institution. Patients underwent Leksell stereotactic head frame placement followed by catheter-based biplane 2-dimensional digital subtraction angiography, 3-dimensional rotational angiography, as well as CBCT-A. The CBCT-A dataset was used for stereotactic planning for GKR. Patients were followed at 1, 3, 6, and 12 months and then annually thereafter. RESULTS: CBCT-A-based targeting was used in 22 consecutive patients. CBCT-A provided detailed spatial resolution and sensitivity of nidal angioarchitecture enabling treatment. The average radiation dose to the margin of the AVM nidus corresponding to the 50% isodose line was 15.6 Gy. No patient had treatment-associated hemorrhage. At early follow-up (mean, 16 months), 84% of patients had a decreasing or obliterated AVM nidus. CONCLUSION: CBCT-A-guided radiosurgery is feasible and useful because it provides sufficient detailed resolution and sensitivity for imaging brain AVMs.

Wall shear stress association with rupture status in volume matched sidewall aneurysms.

OBJECTIVE: Flow induced tangential wall shear stress (WSS) is thought to be involved in aneurysm formation, growth, and rupture. Low WSS was previously associated with rupture, but definitive quantitative analyses remain scant as larger aneurysms are associated with lower WSS regardless of rupture status, and ruptured aneurysms are larger than unruptured aneurysms. Here, the intra-dome WSS was evaluated on 18 internal carotid artery aneurysms, volume matched as ruptured/unruptured pairs in order to remove the confounding effect of size dependence. METHODS: Computational fluid dynamic simulations were performed and WSS was evaluated at peak systole, end diastole, and as time averaged over the cardiac cycle. WSS logarithmic scaling was applied to refine value discrimination at extrema. Ruptured/unruptured lesions were statistically evaluated using pairwise t test analysis. The effect of size on WSS was evaluated in parametric models. RESULTS: In parametric data, there was a statistically significant negative correlation between volume and WSS values. In patient data, mean WSS was not statistically significant but low range WSS values were significantly lower for ruptured aneurysms, regardless of WSS evaluation (time averaged, peak systole, end diastole). Statistically, logarithmic WSS performed better than WSS, with minimum logarithmic WSS at end diastole being the best rupture status discriminator (p=0.001, area under the curve=0.98). Higher range and maximal WSS were not significantly significant. CONCLUSIONS: Aneurysm size is a confounding factor to WSS rupture discrimination, and volume matched analysis is necessary for unbiased evaluation. While these results lend support to the hypothesis that lower WSS induces wall changes which may be associated with rupture, it raises questions regarding the extent of this association, which requires further exploration.