Publications by authors named "Staffan Holmin"

84 Publications

Safety and Outcomes of Thrombectomy in Ischemic Stroke With vs Without Intravenous Thrombolysis.

Neurology 2021 Jun 4. Epub 2021 Jun 4.

Department of Clinical Neuroscience, Karolinska Institutet.

Objective: To test the hypothesis that intravenous thrombolysis (IVT) treatment prior to endovascular thrombectomy (EVT) is associated with better outcomes in patients with anterior circulation large artery occlusion (LAO) stroke, we examined a large real-world database, the SITS-International Stroke Thrombectomy Register (SITS-ISTR).

Methods: We identified centers recording ≥10 consecutive patients in the SITS-ISTR, with at least 70% available modified Rankin Scale (mRS) scores at 3 months during 2014-19. We defined LAO as intracranial internal carotid artery, first and second segment of middle cerebral artery and first segment of anterior cerebral artery. Main outcomes were functional independence (mRS 0-2) and death at 3 months and symptomatic intracranial hemorrhage (SICH) per modified SITS-MOST. We performed propensity score matched (PSM) and multivariable logistic regression analyses.

Results: Of 6350 patients from 42 centers, 3944 (62.1%) received IVT. IVT+EVT treated patients had less frequent atrial fibrillation, ongoing anticoagulation, previous stroke, heart failure and pre-stroke disability. PSM analysis showed that IVT+EVT patients had a higher rate of functional independence than EVT alone patients (46.4% vs. 40.3%, p<0.001) and a lower rate of death at 3 months (20.3% vs. 23.3%, p=0.035). SICH rates (3.5% vs. 3.0%, p= 0.42) were similar in both groups. Multivariate adjustment yielded results consistent with PSM.

Interpretation: Pretreatment with IVT was associated with favorable outcomes in EVT-treated LAO stroke in the SITS Thrombectomy Registry. These findings, while indicative of international routine clinical practice, are limited by observational design, unmeasured confounding and possible residual confounding by indication.

Classification Of Evidence: This study provides Class II evidence that IVT prior to EVT increases the probability of functional independence at 3 months compared to EVT alone.
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http://dx.doi.org/10.1212/WNL.0000000000012327DOI Listing
June 2021

Outcomes in young adults with acute ischemic stroke undergoing endovascular thrombectomy: A real-world multicenter experience.

Eur J Neurol 2021 May 6. Epub 2021 May 6.

Division of Interventional Radiology, Department of Diagnostic Imaging, National University Health System, Singapore City, Singapore.

Endovascular thrombectomy (EVT) is the standard of care for anterior circulation acute ischemic stroke (AIS) with large vessel occlusion (LVO). Young patients with AIS-LVO have distinctly different underlying stroke mechanisms and etiologies. Much is unknown about the safety and efficacy of EVT in this population of young AIS-LVO patients. All consecutive AIS-LVO patients aged 50 years and below were included in this multicenter cohort study. The primary outcome measured was functional recovery at 90 days, with modified Rankin Scale of 0-2 deemed as good functional outcome. A total of 275 AIS-LVO patients that underwent EVT from 10 tertiary centers in Germany, Sweden, Singapore, and Taiwan were included. Successful reperfusion was achieved in 85.1% (234/275). Good functional outcomes were achieved in 66.0% (182/275). Arterial dissection was the most prevalent stroke etiology (42/195, 21.5%). National Institutes of Health Stroke Scale (NIHSS) score at presentation was inversely related to good functional outcomes (aOR: 0.92, 95% CI: 0.88-0.96 per point increase, p < 0.001). Successful reperfusion (aOR: 3.22, 95% CI: 1.44-7.21, p = 0.005), higher ASPECTS (aOR: 1.21, 95% CI: 1.01-1.44, p = 0.036), and bridging intravenous thrombolysis (aOR: 2.37, 95% CI: 1.29-4.34, p = 0.005) independently predicted good functional outcomes. Successful reperfusion was inversely associated with in-hospital mortality (aOR: 0.14, 95% CI: 0.03-0.57, p = 0.006). History of hypertension strongly predicted in-hospital mortality (aOR: 4.59, 95% CI: 1.10-19.13, p = 0.036). While differences in functional outcomes exist across varying stroke aetiologies, high rates of successful reperfusion and good outcomes are generally achieved in young AIS-LVO patients undergoing EVT.
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http://dx.doi.org/10.1111/ene.14899DOI Listing
May 2021

Micro-biopsy for detection of gene expression changes in ischemic swine myocardium: A pilot study.

PLoS One 2021 28;16(4):e0250582. Epub 2021 Apr 28.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Micro-endomyocardial biopsy (micro-EMB) is a novel catheter-based biopsy technique, aiming to increase flexibility and safety compared to conventional EMB. The technique was developed and evaluated in healthy swine. Therefore, the ability to detect disease related tissue changes could not be evaluated. The aim of the present pilot study was to investigate the ability to detect disease related gene expression changes using micro-EMB. Myocardial infarction was induced in three swine by coronary artery balloon occlusion. Micro-EMB samples (n = 164) were collected before, during, and after occlusion. RNA-sequencing was performed on 85 samples, and 53 of these were selected for bioinformatic analysis. A large number of responding genes was detected from the infarcted area (n = 1911). The early responding genes (n = 1268) were mostly related to apoptosis and inflammation. There were fewer responding genes two days after infarction (n = 6), which were related to extra-cellular matrix changes, and none after 14 days. In contrast to the infarcted area, samples harvested from a non-infarcted myocardial region showed considerably fewer regulated genes (n = 33). Deconvolution analysis, to estimate the proportion of different cell types, revealed a higher proportion of fibroblasts and a reduced proportion of cardiomyocytes two days after occlusion compared to baseline (p < 0.02 and p < 0.01, respectively. S5 File). In conclusion, this pilot study demonstrates the capabilities of micro-EMB to detect local gene expression responses at an early stage after ischemia, but not at later timepoints.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0250582PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081259PMC
April 2021

The SITS Open Study: A Prospective, Open Label Blinded Evaluation Study of Thrombectomy in Clinical Practice.

Stroke 2021 Mar 10;52(3):792-801. Epub 2021 Feb 10.

Department of Clinical Neuroscience (N.A., S.H., N.W.), Karolinska Institutet, Stockholm, Sweden.

Background And Purpose: We designed SITS (Safe Implementation of Treatment in Stroke) Open to determine benefit and safety of thrombectomy in clinical practice for large artery occlusion stroke, using selected stent retrievers plus standard care versus standard care alone.

Methods: SITS Open was a prospective, open, blinded evaluation, international, multicenter, controlled, nonrandomized registry study. Centers lacking access to thrombectomy contributed controls. Primary end point was categorical shift in modified Rankin Scale score at 3 months in the per protocol (PP) population. Principal secondary outcomes were symptomatic intracranial hemorrhage, functional independency (modified Rankin Scale score 0-2) and death at 3 months. Patients independently evaluated by video-recorded modified Rankin Scale interviews blinded to treatment or center identity by central core laboratory were regarded as PP population. Propensity score matching with covariate adjusted analysis was performed.

Results: During 2014 to 2017, 293 patients (257 thrombectomy, 36 control) from 26 centers in 10 countries fulfilled intention-to-treat and 200 (170 thrombectomy, 30 control) PP criteria; enrollment of controls was limited by rapid uptake of thrombectomy. In PP analysis, median age was 71 versus 71 years, and baseline National Institutes of Health Stroke Scale 17 versus 17 in the thrombectomy and control arms, respectively. The propensity score matching analysis for PP showed a significant shift for modified Rankin Scale at 3 months favoring the thrombectomy group (odds ratio, 3.8 [95% CI, 1.61-8.95]; =0.002). Regarding safety, there were 4 cases of symptomatic intracranial hemorrhage in the thrombectomy group (2.4%) and none in the control group.

Conclusions: In clinical practice, thrombectomy for patients with large artery occlusion stroke is superior to standard of care in our study. Registration: URL: https://www.clinicaltrials.gov. Unique Identifier: NCT02326428.
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http://dx.doi.org/10.1161/STROKEAHA.120.031031DOI Listing
March 2021

[Ga]ABY-028: an albumin-binding domain (ABD) protein-based imaging tracer for positron emission tomography (PET) studies of altered vascular permeability and predictions of albumin-drug conjugate transport.

EJNMMI Res 2020 Sep 22;10(1):106. Epub 2020 Sep 22.

Department of Clinical Neuroscience, Karolinska Institutet, SE17177, Stockholm, Sweden.

Background: Albumin is commonly used as a carrier platform for drugs to extend their circulatory half-lives and influence their uptake into tissues that have altered permeability to the plasma protein. The albumin-binding domain (ABD) protein, which binds in vivo to serum albumin with high affinity, has proven to be a versatile scaffold for engineering biopharmaceuticals with a range of binding capabilities. In this study, the ABD protein equipped with a mal-DOTA chelator (denoted ABY-028) was radiolabeled with gallium-68 (Ga). This novel radiotracer was then used together with positron emission tomography (PET) imaging to examine variations in the uptake of the ABD-albumin conjugate with variations in endothelial permeability.

Results: ABY-028, produced by peptide synthesis in excellent purity and stored at - 20 °C, was stable for 24 months (end of study). [Ga]ABY-028 could be obtained with labeling yields of > 80% and approximately 95% radiochemical purity. [Ga]ABY-028 distributed in vivo with the plasma pool, with highest radioactivity in the heart ventricles and major vessels of the body, a gradual transport over time from the circulatory system into tissues and elimination via the kidneys. Early [Ga]ABY-028 uptake differed in xenografts with different vascular properties: mean standard uptake values (SUV) were initially 5 times larger in FaDu than in A431 xenografts, but the difference decreased to 3 after 1 h. Cutaneously administered, vasoactive nitroglycerin increased radioactivity in the A431 xenografts. Heterogeneity in the levels and rates of increases of radioactivity uptake was observed in sub-regions of individual MMTV-PyMT mammary tumors and in FaDu xenografts. Higher uptake early after tracer administration could be observed in lower metabolic regions. Fluctuations in the increased permeability for the tracer across the blood-brain-barrier (BBB) direct after experimentally induced stroke were monitored by PET and the increased uptake was confirmed by ex vivo phosphorimaging.

Conclusions: [Ga]ABY-028 is a promising new tracer for visualization of changes in albumin uptake due to disease- and pharmacologically altered vascular permeability and their potential effects on the passive uptake of targeting therapeutics based on the ABD protein technology.
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http://dx.doi.org/10.1186/s13550-020-00694-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509035PMC
September 2020

Molecular Imaging of Inflammation in a Mouse Model of Atherosclerosis Using a Zirconium-89-Labeled Probe.

Int J Nanomedicine 2020 14;15:6137-6152. Epub 2020 Aug 14.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, BioClinicum, Karolinska Institutet, Stockholm, SE 17176, Sweden.

Background: Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions.

Materials And Methods: Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 (Zr). The targeting potential of this probe was compared with unspecific Zr-HSA and F-FDG in an experimental model of atherosclerosis ( mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls.

Results: PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of Zr-Mal-HSA in the atherosclerotic lesions of mice. The maximum standardized uptake values (SUV) for Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (<0.05) in mice than in control WT mice, whereas no difference in SUV was observed for F-FDG in the same animals. Zr-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher (<0.01) for mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher (<0.001) for Zr-Mal-HSA compared with unspecific Zr-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of Zr-Mal-HSA in the aortas of mice than in WT mice (9.4±1.4 vs 0.8±0.3%; <0.001).

Conclusion: Zr radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of mice, as demonstrated by quantitative in vivo PET/MRI. Zr-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis.
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http://dx.doi.org/10.2147/IJN.S256395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434576PMC
November 2020

Left ventricular systolic dysfunction is associated with poor functional outcomes after endovascular thrombectomy.

J Neurointerv Surg 2021 Jun 3;13(6):515-518. Epub 2020 Sep 3.

Department of Neuroradiology, University Hospital Leipzig, Leipzig, Germany.

Background: Endovascular thrombectomy (ET) has transformed acute ischemic stroke (AIS) therapy in patients with large vessel occlusion (LVO). Left ventricular systolic dysfunction (LVSD) decreases global cerebral blood flow and predisposes to hypoperfusion. We evaluated the relationship between LVSD, as measured by LV ejection fraction (LVEF), and clinical outcomes in patients with anterior cerebral circulation LVO who underwent ET.

Methods: This multicenter retrospective cohort study examined anterior circulation LVO AIS patients from six international stroke centers. LVSD was measured by assessment of the echocardiographic LVEF using Simpson's biplane method of discs according to international guidelines. LVSD was defined as LVEF <50%. The primary outcome was defined as a good functional outcome using a modified Rankin Scale (mRS) of 0-2 at 3 months.

Results: We included 440 AIS patients with LVO who underwent ET. On multivariate analyses, pre-existing diabetes mellitus (OR 2.05, 95% CI 1.24 to 3.39;p=0.005), unsuccessful reperfusion (Treatment in Cerebral Infarction (TICI) grade 0-2a) status (OR 4.21, 95% CI 2.04 to 8.66; p<0.001) and LVSD (OR 2.08, 95% CI 1.18 to 3.68; p=0.011) were independent predictors of poor functional outcomes at 3 months. On ordinal (shift) analyses, LVSD was associated with an unfavorable shift in the mRS outcomes (OR 2.32, 95% CI 1.52 to 3.53; p<0.001) after adjusting for age and ischemic heart disease.

Conclusion: Anterior circulation LVO AIS patients with LVSD have poorer outcomes after ET, suggesting the need to consider cardiac factors for ET, the degree of monitoring and prognostication post-procedure.
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http://dx.doi.org/10.1136/neurintsurg-2020-016216DOI Listing
June 2021

De novo arteriovenous shunts after endovascular cure of cerebrospinal macro arteriovenous fistulas. A role for the vasa vasorum?

J Neuroradiol 2021 Mar 27;48(2):127-131. Epub 2020 Jun 27.

Department of Diagnostic and Interventional Neuroradiology, Hôpital Foch, Suresnes, France. Electronic address:

Background And Purpose: Macro-arteriovenous fistulas (MAVFs) are arteriovenous shunts draining into a giant venous ectasia. They can be treated by surgery or embolisation. Angiographic controls are usually performed rapidly after treatment in order to prove the cure of the lesion but no long term angiographies are generally scheduled. We wanted to control the stabilities of such lesions at follow-up.

Method: Clinical history and imaging of ninety-five patients with high flow shunts draining into venous ectasias (MAVFs, Vein of Galen malformations and dilatations) were reviewed.

Results: De novo arteriovenous shunts related to angiogenesis involving vasa vasorum developed in three patients with MAVFs at various intervals. Genetic underlying conditions as HHT or RASA 1 mutations were suspected in each patient.

Conclusions: Neo-angiogenesis can occur after cure of MAVFs. Long term imaging follow-ups should be considered as the natural history of such recurrent shunts is currently unknown.
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http://dx.doi.org/10.1016/j.neurad.2020.06.004DOI Listing
March 2021

Feasibility of unconstrained three-material decomposition: imaging an excised human heart using a prototype silicon photon-counting CT detector.

Eur Radiol 2020 Nov 25;30(11):5904-5912. Epub 2020 Jun 25.

Department of Physics, AlbaNova University Center, KTH Royal Institute of Technology, SE-106 91, Stockholm, Sweden.

Rationale And Objectives: The purpose of this study was to evaluate the feasibility of unconstrained three-material decomposition in a human tissue specimen containing iodinated contrast agent, using an experimental multi-bin photon-counting silicon detector. It was further to evaluate potential added clinical value compared to a 1st-generation state-of-the-art dual-energy computed tomography system.

Materials And Methods: A prototype photon-counting silicon detector in a bench-top setup for x-ray tomographic imaging was calibrated using a multi-material calibration phantom. A heart with calcified plaque was obtained from a deceased patient, and the coronary arteries were injected with an iodinated contrast agent mixed with gelatin. The heart was imaged in the experimental setup and on a 1st-generation state-of-the-art dual-energy computed tomography system. Projection-based three-material decomposition without any constraints was performed with the photon-counting detector data, and the resulting images were compared with those obtained from the dual-energy system.

Results: The photon-counting detector images show better separation of iodine and calcium compared to the dual-energy images. Additional experiments confirmed that unbiased estimates of soft tissue, calcium, and iodine could be achieved without any constraints.

Conclusion: The proposed experimental system could provide added clinical value compared to current dual-energy systems for imaging tasks where mix-up of iodine and calcium is an issue, and the anatomy is sufficiently small to allow iodine to be differentiated from calcium. Considering its previously shown count rate capability, these results show promise for future integration of this detector in a clinical CT scanner.

Key Points: • Spectral photon-counting detectors can solve some of the fundamental problems with conventional single-energy CT. • Dual-energy methods can be used to differentiate iodine and calcium, but to do so must rely on constraints, since solving for three unknowns with only two measurements is not possible. Photon-counting detectors can improve upon these methods by allowing unconstrained three-material decomposition. • A prototype photon-counting silicon detector with high count rate capability allows performing unconstrained three-material decomposition and qualitatively shows better differentiation of iodine and calcium than dual-energy CT.
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http://dx.doi.org/10.1007/s00330-020-07017-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554013PMC
November 2020

Dual-Energy CT Follow-Up After Stroke Thrombolysis Alters Assessment of Hemorrhagic Complications.

Front Neurol 2020 19;11:357. Epub 2020 May 19.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

We aimed to determine whether dual-energy CT (DECT) follow-up can differentiate contrast staining (CS) from intracranial hemorrhage (ICH) in stroke patients treated with intravenous thrombolysis (IVT), who had undergone acute stroke imaging using CT angiography (CTA), and CT perfusion (CTP). : Between November 2012 and January 2018, 168 patients at our comprehensive stroke center underwent DECT follow-up within 36 h after IVT and acute CTA with or without CTP but did not receive intra-arterial imaging or treatment. Two independent readers evaluated plain monochromatic CT (pCT) alone and compared this with a second reading of a combined DECT approach using pCT and water- and iodine-weighted images, establishing and grading the ICH diagnosis, per Heidelberg and Safe Implementation of Treatments in Stroke Monitoring Study (SITS-MOST) classifications. On pCT alone within 36 h, 31/168 (18.5%) patients had findings diagnosed as ICH. Using combined DECT (cDECT) changed ICH diagnosis to "CS only" in 3/168 (1.8%) patients, constituting 3/31 (9.7%) of cases with initially pCT-diagnosed ICH. These three cases had pCT diagnoses of one SAH, one minor, and one more extensive petechial hemorrhage (hemorrhagic infarction types 1 and 2), respectively. pCT alone had a 100% sensitivity, 98% specificity, 90% positive predictive value (PPV), 100% negative predictive value (NPV), and 98% accuracy for any ICH, compared to the cDECT. Inter-reader agreement for ICH classification using pCT compared to DECT was weighted kappa 0.92 (95% CI 0.87-0.98) vs. 0.91 (0.85-0.95). Compared to pCT, DECT within 36 h after IV thrombolysis for acute ischemic stroke, changes the radiological diagnosis of post-treatment ICH to "CS only" in a small proportion of patients. Studies are warranted of whether the altered radiological reports have an impact on patient management, for example initiation timing of antithrombotic secondary prevention.
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http://dx.doi.org/10.3389/fneur.2020.00357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249255PMC
May 2020

The cellular basis of increased PET hypoxia tracer uptake in focal cerebral ischemia with comparison between [F]FMISO and [Cu]CuATSM.

J Cereb Blood Flow Metab 2021 Mar 19;41(3):617-629. Epub 2020 May 19.

The Department of Clinical Neuroscience, Karolinska Institutet, Stockholm Sweden.

PET hypoxia imaging can assess tissue viability in acute ischemic stroke (AIS). [F]FMISO is an established tracer but requires substantial accumulation time, limiting its use in hyperacute AIS. [Cu]CuATSM requires less accumulation time and has shown promise as a hypoxia tracer. We compared these tracers in a M2-occlusion model (M2CAO) with preserved collateral blood flow. Rats underwent M2CAO and [F]FMISO ( = 12) or [Cu]CuATSM ( = 6) examinations. [Cu]CuATSM animals were also examined with MRI. Pimonidazole was used as a surrogate for [F]FMISO in an immunofluorescence analysis employed to profile levels of hypoxia in neurons (NeuN) and astrocytes (GFAP). There was increased [F]FMISO uptake in the M2CAO cortex. No increase in [Cu]CuATSM activity was found. The pimonidazole intensity of neurons and astrocytes was increased in hypoxic regions. The pimonidazole intensity ratio was higher in neurons than in astrocytes. In the majority of animals, immunofluorescence revealed a loss of astrocytes within the core of regions with increased pimonidazole uptake. We conclude that [F]FMISO is superior to [Cu]CuATSM in detecting hypoxia in AIS, consistent with an earlier study. [F]FMISO may provide efficient diagnostic imaging beyond the hyperacute phase. Results do not provide encouragement for the use of [Cu]CuATSM in experimental AIS.
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http://dx.doi.org/10.1177/0271678X20923857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7922752PMC
March 2021

Myocardial micro-biopsy procedure for molecular characterization with increased precision and reduced trauma.

Sci Rep 2020 05 15;10(1):8029. Epub 2020 May 15.

Department of Clinical Neuroscience, Karolinska Institutet, Solna, Sweden.

Endomyocardial biopsy is a valuable tool in cardiac diagnostics but is limited by low diagnostic yield and significant complication risks. Meanwhile, recent developments in transcriptomic and proteomic technologies promise a wealth of biological data from minimal tissue samples. To take advantage of the minimal tissue amount needed for molecular analyses, we have developed a sub-millimeter endovascular biopsy device, considerably smaller than current clinical equipment, and devised a low-input RNA-sequencing protocol for analyzing small tissue samples. In in vivo evaluation in swine, 81% of biopsy attempts (n = 157) were successful. High quality RNA-sequencing data was generated from 91% of the sequenced cardiac micro-biopsy samples (n = 32). Gene expression signatures of samples taken with the novel device were comparable with a conventional device. No major complications were detected either during procedures or during 7 days' follow-up, despite acquiring a relatively large number of biopsies (median 30) in each animal. In conclusion, the novel device coupled with RNA-sequencing provides a feasible method to obtain molecular data from the myocardium. The method is less traumatic and has a higher flexibility compared to conventional methods, enabling safer and more targeted sampling from different parts of the myocardium.
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http://dx.doi.org/10.1038/s41598-020-64900-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229024PMC
May 2020

Significant aortic stenosis associated with poorer functional outcomes in patients with acute ischaemic stroke undergoing endovascular therapy.

Interv Neuroradiol 2020 Dec 27;26(6):793-799. Epub 2020 Apr 27.

Division of Neurology, Department of Medicine, National University Health System, Singapore, Singapore.

Background And Aim: Bi-directional feedback mechanisms exist between the heart and brain, which have been implicated in heart failure. We postulate that aortic stenosis may alter cerebral haemodynamics and influence functional outcomes after endovascular thrombectomy for acute ischaemic stroke. We compared clinical characteristics, echocardiographic profile and outcomes in patients with or without aortic stenosis that underwent endovascular thrombectomy for large vessel occlusion acute ischaemic stroke.

Methods: Consecutive acute ischaemic stroke patients with anterior and posterior circulation large vessel occlusion (internal carotid artery, middle cerebral artery and basilar artery) who underwent endovascular thrombectomy were studied. Patients were divided into those with significant aortic stenosis (aortic valve area <1.5 cm) and without. Univariate and multivariate analyses were employed to compare and determine predictors of functional outcomes measured by modified Rankin scale at three months.

Results: We identified 26 (8.5%) patients with significant aortic stenosis. These patients were older (median age 76 (interquartile range 68-84) vs. 67 (interquartile range 56-75) years,  = 0.001), but similar in terms of medical comorbidities and echocardiographic profile. Rates of successful recanalisation (73.1% vs. 78.0%), symptomatic intracranial haemorrhage (7.7% and 7.9%) and mortality (11.5% vs. 12.6%) were similar. Significant aortic stenosis was independently associated with poorer functional outcome (modified Rankin scale >2) at three months (adjusted odds ratio 2.7, 95% confidence interval 1.1-7.5,  = 0.048), after adjusting for age, door-to-puncture times, stroke severity and rates of successful recanalisation.

Conclusion: In acute ischaemic stroke patients managed with endovascular thrombectomy, significant aortic stenosis is associated with poor functional outcome despite comparable recanalisation rates. Larger cohort studies are needed to explore this relationship further.
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http://dx.doi.org/10.1177/1591019920920988DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724604PMC
December 2020

Implementation of a Prehospital Stroke Triage System Using Symptom Severity and Teleconsultation in the Stockholm Stroke Triage Study.

JAMA Neurol 2020 06;77(6):691-699

Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.

Importance: To our knowledge, it is unknown whether a prehospital stroke triage system combining symptom severity and teleconsultation could accurately select patients for primary stroke center bypass and hasten delivery of endovascular thrombectomy (EVT) without delaying intravenous thrombolysis (IVT).

Objective: To evaluate the predictive performance of the newly implemented Stockholm Stroke Triage System (SSTS) for large-artery occlusion (LAO) stroke and EVT initiation. Secondary objectives included evaluating whether the Stockholm Stroke Triage System shortened onset-to-puncture time for EVT and onset-to-needle time (ONT) for IVT.

Design, Setting, And Participants: This population-based prospective cohort study conducted from October 2017 to October 2018 across the Stockholm region (Sweden) included patients transported by first-priority ("code stroke") ambulance to the hospital for acute stroke suspected by an ambulance nurse and historical controls (October 2016-October 2017). Exclusion criteria were in-hospital stroke and helicopter or private transport. Of 2909 eligible patients, 4 (0.14%) declined participation.

Exposures: Patients were assessed by ambulance nurses with positive the face-arm-speech-time test or other stroke suspicion and were evaluated for moderate-to-severe hemiparesis (≥2 National Institutes of Health stroke scale points each on the ipsilateral arm and leg [A2L2 test]). If present, the comprehensive stroke center (CSC) stroke physician was teleconsulted by phone for confirmation of stroke suspicion, assessment of EVT eligibility, and direction to CSC or the nearest primary stroke center. If absent, the nearest hospital was prenotified.

Main Outcomes And Measures: Primary outcome: LAO stroke. Secondary outcomes: EVT initiation, onset-to-puncture time, and ONT. Predictive performance measures included sensitivity, specificity, positive and negative predictive values, the overall accuracy for LAO stroke, and EVT initiation.

Results: We recorded 2905 patients with code-stroke transports (1420 women [49%]), and of these, 323 (11%) had A2L2+ teleconsultation positive results and were triaged for direct transport to CSC (median age, 73 years [interquartile range (IQR), 64-82 years]; 55 women [48%]). Accuracy for LAO stroke was 87% (positive predictive value, 41%; negative predictive value, 93%) and 91% for EVT initiation (positive predictive value, 26%; negative predictive value, 99%). Endovascular thrombectomy was performed for 84 of 323 patients (26%) with triage-positive results and 35 of 2582 patients (1.4%) with triage-negative results. In EVT cases with a known onset time (77 [3%]), the median OPT was 137 minutes (IQR, 118-180; previous year, 206 minutes [IQR, 160-280]; n = 75) (P < .001). The regional median ONT (337 [12%]) was unchanged at 115 minutes (IQR, 83-164; previous year, 115 minutes [IQR, 85-161]; n = 360) (P = .79). The median CSC IVT door-to-needle time was 13 minutes (IQR, 10-18; 116 [4%]) (previous year, 31 minutes [IQR, 19-38]; n = 45) (P < .001).

Conclusions And Relevance: The Stockholm Stroke Triage System, which combines symptom severity and teleconsultation, results in markedly faster EVT delivery without delaying IVT.
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http://dx.doi.org/10.1001/jamaneurol.2020.0319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136864PMC
June 2020

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

Lancet 2020 03 20;395(10227):878-887. Epub 2020 Feb 20.

McMaster University, Hamilton, ON, Canada.

Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke.

Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018.

Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups.

Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo.

Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO.
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http://dx.doi.org/10.1016/S0140-6736(20)30258-0DOI Listing
March 2020

Oxygen metabolism MRI - A comparison with perfusion imaging in a rat model of MCA branch occlusion and reperfusion.

J Cereb Blood Flow Metab 2020 11 16;40(11):2315-2327. Epub 2019 Dec 16.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

The penumbra is sustained by an increased extraction of oxygen (OEF) from blood to brain tissue. Metabolic imaging may improve penumbra specificity when examining stroke patients with wake-up stroke and a long time between admission and symptom onset. We used MRI to examine OEF, and compared the volume of regions with elevated OEF to the volume of regions with perfusion deficit in a M2 occlusion model (M2CAO) with preserved collateral blood flow. OEF was calculated from BOLD MRI examining tissue R2', with ASL perfusion imaging employed to determine cerebral blood flows (CBF) and volumes. Diffusion imaging was used to identify the ischemic core (IC). Examinations were performed during and after transient M2CAO in rats. The IC-OEF mismatch was significantly smaller than the IC-CBF mismatch during M2CAO. The penumbra OEF was significantly increased during M2CAO, and decreased significantly after reperfusion. The IC-OEF mismatch may provide increased penumbra specificity compared to IC-CBF mismatch regimens. Results strongly indicate the potential of metabolic MRI for thrombectomy patient selection in cases with a long time from symptom onset to admission. Results demonstrate the effectiveness of reperfusion in alleviating metabolic disturbances in ischemic regions, emphasizing fast treatment to achieve significant neurological recovery in stroke patients.
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http://dx.doi.org/10.1177/0271678X19892271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7585917PMC
November 2020

Blood Pressure After Endovascular Thrombectomy: Modeling for Outcomes Based on Recanalization Status.

Stroke 2020 02 11;51(2):519-525. Epub 2019 Dec 11.

From the Department of Clinical Neuroscience (M. Matusevicius, C.C., M. Mazya, T.M., S.H., N.A.), Karolinska Institutet, Stockholm, Sweden.

Background and Purpose- The optimal level for blood pressure after endovascular thrombectomy in acute ischemic stroke is not well established. We sought to evaluate the association of post-endovascular thrombectomy systolic blood pressure (SBP) levels with clinical outcomes. Methods- We included endovascular thrombectomy-treated patients registered from 2014 to 2017 in the Safe Implementation of Treatments in Stroke International Thrombectomy Registry. The mean 24-hour SBP after endovascular thrombectomy treatment was analyzed both as a continuous variable and in intervals. The primary outcome was 3-month functional independence (modified Rankin Scale score of 0-2). The secondary outcomes were symptomatic intracerebral hemorrhage (SICH) and 3-month mortality. The SBP interval with the highest proportion of functional independence was chosen as reference. All analyses were performed for successful or unsuccessful recanalization (modified Treatment in Cerebral Ischemia score ≥2b or <2b, respectively). The results were adjusted for known confounders in logistic regression models. Results- In the multivariable analyses, a higher SBP value as a continuous variable was associated unfavorably with all outcomes in patients with successful recanalization (n=2920) and with more SICH in patients with unsuccessful recanalization (n=711). SBP interval ≥160 mm Hg was associated with less functional independence (adjusted odds ratio, 0.28 [95% CIs, 0.15-0.53]) and more SICH (adjusted odds ratio, 6.82 [95% CIs, 1.53-38.09]) compared with reference 100 to 119 mm Hg in patients with successful recanalization. SBP ≥160 mm Hg was associated with more SICH (adjusted odds ratio, 6.62 [95% CIs, 1.07-51.05]) compared with reference 120 to 139 mm Hg in patients with unsuccessful recanalization. Conclusions- Higher SBP values were associated with less functional independence at 3 months in patients with successful recanalization and with more SICH regardless of recanalization status.
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http://dx.doi.org/10.1161/STROKEAHA.119.026914DOI Listing
February 2020

Preclinical Toxicity Evaluation of Clinical Grade Placenta-Derived Decidua Stromal Cells.

Front Immunol 2019 19;10:2685. Epub 2019 Nov 19.

Translational Cell Therapy Research (TCR), Department of Clinical Science Intervention and Technology (CLINTEC), Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Placenta-derived decidua stromal cells (DSCs) are being investigated as an alternative to other sources of mesenchymal stromal cells (MSCs) for cellular therapy. DSCs are more effective in treating acute inflammatory diseases in human and this is our preclinical safety study of human DSCs in Sprague-Dawley rats and Balb/c mice. Human DSCs were cultured and expanded from fetal membranes obtained from placentas following cesarean section. In rats, 0.5 × 10 cells/kg were injected intravenously ( = 4) or intra-aortal ( = 4). In mice, DSCs were given intravenously at doses ranging from 4-40 × 10 cells/kg (total of = 120 mice). tracking of human cells in mice was performed by using transduced DSC with luciferin gene, and in rats by using F-FDG PET. Clotting parameters were determined and . All intra-arterially DSC-treated rats had normal motility and behavior and histological examination was normal for liver, spleen kidneys and thigh muscles. Mice treated with DSCs showed no immediate or long-term side effects. None of the mice died or showed acute toxicity or adverse reactions 3 and 30 days after DSC infusion. Murine blood biochemistry profiles related to liver, kidney, heart, and inflammatory indices was not influenced by DSC infusion and complete blood counts were normal. tracking of infused DSCs detected a signal in the lungs for up to 4 days post infusion. Compared to bone marrow derived MSCs, the DSCs had better viability, smaller size, but stronger clotting in human blood and plasma. Both MSC- and DSC-induced coagulation and complement activation markers, thrombin-anti-thrombin complex (TAT) and C3a, and clotting parameters were decreased by heparin supplementation. In conclusion, DSCs are safe with almost no side effects even with doses 40 times higher than are used clinically, particularly when supplemented with low-dose heparin.
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http://dx.doi.org/10.3389/fimmu.2019.02685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6877599PMC
November 2020

The EXPANd trial: effects of exercise and exploring neuroplastic changes in people with Parkinson's disease: a study protocol for a double-blinded randomized controlled trial.

BMC Neurol 2019 Nov 12;19(1):280. Epub 2019 Nov 12.

Department of Neurobiology, Care sciences and Society, Division of Physiotherapy, Karolinska Institutet, Stockholm, Sweden.

Background: Parkinson's disease (PD) affects many physiological systems essential for balance control. Recent studies suggest that intensive and cognitively demanding physical exercise programs are capable of inducing plastic brain changes in PD. We have developed a highly challenging balance training (the HiBalance) program that emphasizes critical aspects of balance control through progressively introducing more challenging exercises which incorporates dual-tasking. Earlier studies have shown it to be effective in improving balance, gait and dual-tasking. The study design has thereafter been adjusted to link intervention-induced behavioral changes to brain morphology and function. Specifically, in this randomized controlled trial, we will determine the effects of the HiBalance program on balance, gait and cognition and relate this to task-evoked functional MRI (fMRI), as well as brain-derived neurotrophic factor (BDNF) in participants with mild-moderate PD.

Methods: One hundred participants with idiopathic PD, Hoehn & Yahr stage 2 or 3, ≥ 60 years of age, ≥ 21 on Montreal Cognitive Assessment will be recruited in successive waves and randomized into either the HiBalance program or to an active control group (the HiCommunication program, targeting speech and communication). Both interventions will be performed in small groups, twice a week with 1 h sessions for 10 weeks. In addition, a 1 h, once a week, home exercise program will also be performed. A double-blinded design will be used. At the pre- and post-assessments, participants will be assessed on balance (main outcome), gait, cognitive functions, physical activity, voice/speech function, BDNF in serum and fMRI (3 T Philips) during performance of motor-cognitive tasks.

Discussion: Since there is currently no cure for PD, findings of neuroplastic brain changes in response to exercise would revolutionize the way we treat PD, and, in turn, provide new hope to patients for a life with better health, greater independence and improved quality of life.

Trial Registration: ClincalTrials.gov: NCT03213873, first posted July 11, 2017.
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http://dx.doi.org/10.1186/s12883-019-1520-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849188PMC
November 2019

Basilar artery occlusion and unwarranted clinical trials.

Interv Neuroradiol 2020 02 5;26(1):5-6. Epub 2019 Sep 5.

Department of Neuroradiology, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1177/1591019919874568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997994PMC
February 2020

Dual energy CT after stroke thrombectomy alters assessment of hemorrhagic complications.

Neurology 2019 09 13;93(11):e1068-e1075. Epub 2019 Aug 13.

From the Departments of Clinical Neuroscience (H.A., S.H., M.V.M.), Neuroradiology (H.A., S.H.), and Neurology (M.V.M.), Karolinska University Hospital, Stockholm, Sweden.

Objective: To determine whether dual energy CT with a combined approach (cDECT) using a plain noncontrast monochromatic CT (pCT), a water-weighted image after iodine removal, and an iodine-weighted image changes the diagnosis and classification of intracranial hemorrhage (ICH) after endovascular thrombectomy (EVT) in acute ischemic stroke compared to a pCT image alone without separate water and iodine weighting.

Method: During 2012 to 2016, 372 patients at our comprehensive stroke center underwent DECT scans within 36 hours after EVT. Two readers evaluated pCT compared to a second reading with cDECT, establishing the diagnosis of ICH and grading it per the Heidelberg and Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST) classifications.

Result: Using cDECT changed the ICH diagnosis to contrast staining only in 34% (52 of 152), modified the ICH grade in 10% (15 of 152), and diagnosed initially undetected ICH in 2% (5 of 220). pCT alone had 95% sensitivity, 80% specificity, 66% positive predictive value, 98% negative predictive value, and 85% accuracy for ICH compared to cDECT. Interreader agreement on the presence of ICH increased with cDECT compared to pCT (Cohen κ = 0.77 [95% confidence interval 0.69-0.84] vs 0.68 [0.61-0.76]).

Conclusion: cDECT within 36 hours after EVT changes the radiologic report regarding posttreatment ICH in a considerable proportion of patients undergoing EVT compared to pCT alone. This could affect decision-making regarding monitoring, secondary prevention, and prognostication. The cDECT scan could improve the interpretation consistency of high-attenuating changes on post-EVT images.
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http://dx.doi.org/10.1212/WNL.0000000000008093DOI Listing
September 2019

Posterior communicating and anterior communicating arteries on pre-thrombectomy computed tomography scans are associated with good outcomes irrespective of leptomeningeal collateral status.

Interv Neuroradiol 2019 Aug 25;25(4):364-370. Epub 2019 Feb 25.

7 University Hospitals Leuven, Leuven, Belgium.

Background: Collateral blood flow is known to be an important factor that sustains the penumbra during acute stroke. We looked at both the leptomeningeal collateral circulation and the presence of anterior and posterior communicating arteries to determine the factors associated with good outcomes and mortality.

Methods: We included all patients with acute ischaemic stroke in the anterior circulation, who underwent thrombectomy with the same thrombectomy device from 2013 to 2016. We assessed the leptomeningeal circulation by the Tan, Miteff and Maas validated scoring systems on pre-treatment computed tomographic angiography scans and looked at collateral flow through anterior and posterior communicating arteries. The results were good functional outcomes at 3 months (modified Rankin scale 0-2) and mortality.

Results: A total of 147 consecutive acute stroke patients treated with the Embotrap device were included with a median National Institutes of Health stroke scale of 15 (range 2-26). On multivariate analysis only younger age (odds ratio (OR) 0.96/year, 95% confidence interval (CI) 0.94-0.99,  = 0.026), lower National Institutes of Health stroke scale score (OR 0.87/point, 95% CI 0.80-0.93,  < 0.001), number of attempts (OR 0.80/attempt, 95% CI 0.65-0.99,  = 0.043) and the presence of a patent anterior communicating artery (OR 14.03, 95% CI 1.42-139.07,  = 0.024) were associated with good functional outcomes. The number of attempts (OR 1.66/attempt, 95% CI 1.21-2.29,  = 0.002) was significantly associated with mortality and the presence of a patent posterior communicating artery (OR 0.098, 95% CI 0.016-0.59,  = 0.011) was inversely associated with mortality.

Conclusions: Our study shows that the presence of anterior and posterior communicating arteries is significantly associated with good functional outcomes and reduced mortality, respectively, independent of the leptomeningeal circulation status.
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http://dx.doi.org/10.1177/1591019919831215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607609PMC
August 2019

Thrombo-embolic complications in takotsubo syndrome: Review and demonstration of an illustrative case.

Clin Cardiol 2019 Feb 3;42(2):312-319. Epub 2019 Jan 3.

Coronary Artery Disease Area, Heart and Vascular Theme, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Thrombo-embolism is one of the serious complications of takotsubo syndrome (TS) in addition to heart failure, pulmonary edema, cardiogenic shock, cardiac arrest, life-threatening arrhythmias, left ventricular outlet tract obstruction, mitral regurgitation, cardiac rupture, and death. The most common cardio-embolic events in TS are cerebral, renal, and peripheral embolism. Approximately, one-third of patients with left ventricular thrombus (LVT) in TS develop embolic complications. Cardio-embolism in TS may occur with or without the presence of detectable LVT. In the present report, the thrombo-embolic complications in TS with the emphasis on the association of TS to both acute coronary syndrome (ACS) including coronary embolism and ischemic stroke including cerebral embolism are reviewed. This serious complication is elucidated by demonstration of the case of a 67-year-woman with mid-apical TS complicated by LVT, left anterior descending artery (LAD) and left middle cerebral artery (segment M2) thrombo-embolic occlusions. The cerebral artery thrombotic occlusion was treated successfully with endovascular thrombectomy with complete resolution of the neurological deficits. There was spontaneous recanalization of the apical LAD occlusion verified by cardiac computed tomography angiography.
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http://dx.doi.org/10.1002/clc.23137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6712329PMC
February 2019

Very Late Leptomeningeal Collaterals-Potential New Way to Subdivide Modified Thrombolysis in Cerebral Ischemia (mTICI) 2B.

Clin Neuroradiol 2020 Mar 26;30(1):77-83. Epub 2018 Nov 26.

University hospitals Leuven, Leuven, Belgium.

Background: Studies have shown that the modified thrombolysis in cerebral ischemia (mTICI) 2B score is associated with better functional outcome; however, 50-99% reperfusion is a large range and there may be factors which can differentiate this further. The effects of very late leptomeningeal collaterals (VLLC) on mTICI-2B patients were studied.

Method: A prospectively collected registry of anterior circulation AIS patients treated with the EmboTrap revascularization device from 2013 to 2016 was evaluated. Imaging parameters and timings, including the mTICI score were verified by an external core laboratory blinded to the clinical data. The final angiogram was examined for the appearance of VLLC in predicting 3‑month outcomes including excellent functional outcomes, defined as modified Rankin scale (mRS) 0-1, bleeding risk and mortality.

Results: A total of 177 consecutive anterior circulation stroke patients were included in the analysis. Of these 94 (53.1%) achieved only mTICI-2B reperfusion, 16/94 (17.0%) patients achieved excellent functional outcomes at 3 months and 26 (27.7%) had hyperdensity on follow-up computed tomography (CT). On univariate analysis, the presence of VLLC was inversely associated with excellent functional outcomes at 3 months and positively associated with mortality in patients with mTICI-2B reperfusion. On multivariate analysis VLLC was inversely associated with excellent outcomes (odds ratio 0.075, 95% confidence interval 0.007-0.765, P = 0.029) but not associated with mortality.

Conclusion: The mTICI-2B grade may be further refined by secondary radiological markers. The VLLC sign is associated with the loss of excellent functional outcomes at 3 months. It is a simple sign to discriminate mTICI-2B into different grades but should be verified in larger populations from other centers.
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http://dx.doi.org/10.1007/s00062-018-0747-4DOI Listing
March 2020

Pedicle Screw Placement Using Augmented Reality Surgical Navigation With Intraoperative 3D Imaging: A First In-Human Prospective Cohort Study.

Spine (Phila Pa 1976) 2019 04;44(7):517-525

Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.

Study Design: Prospective observational study.

Objective: The aim of this study was to evaluate the accuracy of pedicle screw placement using augmented reality surgical navigation (ARSN) in a clinical trial.

Summary Of Background Data: Recent cadaveric studies have shown improved accuracy for pedicle screw placement in the thoracic spine using ARSN with intraoperative 3D imaging, without the need for periprocedural x-ray. In this clinical study, we used the same system to place pedicle screws in the thoracic and lumbosacral spine of 20 patients.

Methods: The study was performed in a hybrid operating room with an integrated ARSN system encompassing a surgical table, a motorized flat detector C-arm with intraoperative 2D/3D capabilities, integrated optical cameras for augmented reality navigation, and noninvasive patient motion tracking. Three independent reviewers assessed screw placement accuracy using the Gertzbein grading on 3D scans obtained before wound closure. In addition, the navigation time per screw placement was measured.

Results: One orthopedic spinal surgeon placed 253 lumbosacral and thoracic pedicle screws on 20 consenting patients scheduled for spinal fixation surgery. An overall accuracy of 94.1% of primarily thoracic pedicle screws was achieved. No screws were deemed severely misplaced (Gertzbein grade 3). Fifteen (5.9%) screws had 2 to 4 mm breach (Gertzbein grade 2), occurring in scoliosis patients only. Thirteen of those 15 screws were larger than the pedicle in which they were placed. Two medial breaches were observed and 13 were lateral. Thirteen of the grade 2 breaches were in the thoracic spine. The average screw placement time was 5.2 ± 4.1 minutes. During the study, no device-related adverse event occurred.

Conclusion: ARSN can be clinically used to place thoracic and lumbosacral pedicle screws with high accuracy and with acceptable navigation time. Consequently, the risk for revision surgery and complications could be minimized.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0000000000002876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6426349PMC
April 2019

Transcriptomic analysis of the harvested endothelial cells in a swine model of mechanical thrombectomy.

Neuroradiology 2018 Jul 14;60(7):759-768. Epub 2018 May 14.

Department of Clinical Neuroscience, Karolinska Institutet, SE-171 76, Stockholm, Sweden.

Purpose: In mechanical thrombectomy (MT) for ischemic stroke, endothelial cells (ECs) from intracranial blood vessels adhere to the stent retriever device and can be harvested. However, understanding the molecular biology and the role of the endothelium in different pathological conditions remains insufficient. The purpose of the study was to characterize and analyze the molecular aspect of harvested ECs using cell culture and transcriptomic techniques in an MT swine model relevant to clinical ischemic stroke.

Methods: In swine, preformed thrombi were injected into the external carotid and subclavian arteries to occlude their branches. MT was performed according to clinical routine. The stent retriever device and thrombus were treated with cell dissociation buffer. The resulting cell suspension was analyzed by immunohistochemistry and was cultured. Cultured cells were analyzed using single-cell RNA sequencing (scRNA-seq) after fluorescence-activated cell sorting (FACS).

Results: A total number of 37 samples were obtained containing CD31-positive cells. Cell culture was successful in 90% of samples, and the cells expressed multiple typical EC protein markers. Eighty-nine percent of the sorted cells yielded high-quality transcriptomes, and single-cell transcriptomes from cultured cells showed that they expressed typical endothelial gene patterns. Gene expression analysis of ECs from an occluded artery did not show distinctive clustering into subtypes.

Conclusion: ECs harvested during MT can be cultured and analyzed using single-cell transcriptomic techniques. This analysis can be implemented in clinical practice to study the EC gene expression of comorbidities, such as hypertension, diabetes mellitus, and metabolic syndrome, in patients suffering from acute ischemic stroke.
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http://dx.doi.org/10.1007/s00234-018-2033-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5995995PMC
July 2018

Intra-arterial chemotherapy for retinoblastoma in Sweden - evaluation of treatment efficacy and complications.

Acta Ophthalmol 2018 Dec 24;96(8):e1040-e1041. Epub 2018 Apr 24.

Department of Neuroradiology, Karolinska University Hospital Solna, Stockholm, Sweden.

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http://dx.doi.org/10.1111/aos.13796DOI Listing
December 2018

Thrombectomy using the EmboTrap device: core laboratory-assessed results in 201 consecutive patients in a real-world setting.

J Neurointerv Surg 2018 10 24;10(10):964-968. Epub 2018 Mar 24.

Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.

Background: We studied patients treated with the EmboTrap revascularization device in a prospective registry which is core laboratory evaluated by physicians from external centers. The goal was to determine how the EmboTrap would perform under the everyday conditions of a high-volume stroke center.

Methods: We examined all patients with acute stroke treated with the Embotrap device from October 2013 to March 2017 in our center. Imaging parameters and times were adjudicated by core laboratory personnel blinded to clinical information, treating physician, and clinical outcomes. Clinical evaluation was performed by independent neurologists and entered in a national registry. Evaluated endpoints were: successful revascularization (modified Thrombolysis in Cerebral Infarction (mTICI) 2b-3) and good clinical outcomes at 3 months (modified Rankin Scale (mRS) 0-2).

Results: 201 consecutive patients with a median NIH Stroke Scale (NIHSS) score of 15 (range 2-30) were included. 170 patients (84.6%) achieved mTICI 2b-3 reperfusion. The median number of attempts was 2 (range 1-10) with 52.8% of the population achieving good functional outcomes (mRS 0-2) at 3 months. On univariate analysis, good functional outcome was associated with the number of attempts, puncture-to-reperfusion time, anterior circulation occlusion, and NIHSS score. On multivariate analysis, pre-treatment NIHSS (OR 0.845 per point, 95% CI 0.793 to 0.908, P<0.001) and puncture-to-reperfusion time (OR 0.9952 per min, 95% CI 0.9914 to 0.9975, P=0.023) were associated with good functional outcomes at 3 months.

Conclusion: The Embotrap device has a high rate of successful reperfusion. Our core laboratory-audited single-center experience suggests the technical feasibility and safety of the Embotrap for first-line use in a real-world setting.
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http://dx.doi.org/10.1136/neurintsurg-2018-013765DOI Listing
October 2018

Posterior Circulation Occlusions May Be Associated with Distal Emboli During Thrombectomy : Factors for Distal Embolization and a Review of the Literature.

Clin Neuroradiol 2019 Sep 22;29(3):425-433. Epub 2018 Mar 22.

Department of Clinical Neuroscience, Karolinska Institutet and Department of Neuroradiology, Karolinska University Hospital, Solnavägen 1, 171 77, Solna, Stockholm, Sweden.

Background: Distal embolization or movement of the thrombus to previously uninvolved vasculature are feared complications during stroke thrombectomy. We looked at associated factors in a consecutive series of patients who underwent thrombectomy with the same endovascular device.

Methods: We included all patients with acute ischemic stroke in the anterior or posterior circulation, who underwent thrombectomy with the same thrombectomy device for acute stroke from 2013 to 2016. Distal embolization was defined as any movement of the thrombus into a previously uninvolved portion of the cerebral vasculature or the presence of thrombotic material further downstream in the affected vessel, which occurred after the initial angiogram. We studied patient-related as well as technical factors to determine their association with distal emboli.

Results: In this study 167 consecutive acute stroke patients treated with the emboTrap® device (Cerenovus, Irvine, CA, USA) were included with a median National Institutes of Health Stroke Scale (NIHSS) of 15 (range 2-30) and mean age of 67 years (SD 13.1 years). Of the patients in our cohort 20 (11.9%) experienced distal emboli, with 2.3% into a new territory and 9.6% into a territory distal to the primary occlusion. On univariate analysis, age, intravenous tissue plasminogen activator (tPA), posterior circulation occlusions, and general anesthesia were associated with distal emboli. On multivariate analysis, only posterior circulation occlusions (odds ratio OR 4.506 95% confidence interval CI 1.483-13.692, p = 0.008) were significantly associated with distal emboli. Distal embolization was not significantly associated with worse functional outcomes at 3 months, increased mortality or increased bleeding risk.

Conclusion: Posterior circulation occlusions were significantly associated with distal emboli during thrombectomy, possibly due to the lack of flow arrest during such procedures. New techniques and devices should be developed to protect against embolic complications during posterior circulation stroke thrombectomy.
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http://dx.doi.org/10.1007/s00062-018-0679-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6710331PMC
September 2019

Subpixel x-ray imaging with an energy-resolving detector.

J Med Imaging (Bellingham) 2018 Jan 20;5(1):013507. Epub 2018 Mar 20.

Royal Institute of Technology, Department of Physics, Stockholm, Sweden.

The detector pixel size can be a severe limitation in x-ray imaging of fine details in the human body. We demonstrate a method of using spectral x-ray measurements to image the spatial distribution of the linear attenuation coefficient on a length scale smaller than one pixel, based on the fact that interfaces parallel to the x-ray beam have a unique spectral response, which distinguishes them from homogeneous materials. We evaluate the method in a simulation study by simulating projection imaging of the border of an iodine insert with [Formula: see text] in a soft tissue phantom. The results show that the projected iodine profile can be recovered with an RMS resolution of 5% to 34% of the pixel size, using an ideal energy-resolving detector. We also validate this method in an experimental study by imaging an iodine insert in a polyethylene phantom using a photon-counting silicon-strip detector. The results show that abrupt and gradual transitions can be distinguished based on the transmitted x-ray spectrum, in good agreement with simulations. The demonstrated method may potentially be used for improving visualization of blood vessel boundaries, e.g., in acute stroke care.
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http://dx.doi.org/10.1117/1.JMI.5.1.013507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5859671PMC
January 2018