Intranasal Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Hypoxic-Ischemic Brain Injury.

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 108 exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers.

Intracerebral transplantation of MRI-trackable autologous bone marrow stromal cells for patients with subacute ischemic stroke.

BACKGROUND: Ischemic stroke is one of the leading causes of death and neurological disability worldwide, and stem cell therapy is highly expected to reverse the sequelae. This phase 1/2, first-in-human study evaluated the safety, feasibility, and monitoring of an intracerebral-transplanted magnetic resonance imaging (MRI)-trackable autologous bone marrow stromal cell (HUNS001-01) for patients with subacute ischemic stroke. METHODS: The study included adults with severe disability due to ischemic stroke. HUNS001-01 cultured with human platelet lysates and labeled with superparamagnetic iron oxide was stereotactically transplanted into the peri-infarct area 47-64 days after ischemic stroke onset (dose: 2 or 5 × 107 cells). Neurological and radiographic evaluations were performed throughout 1 year after cell transplantation. The trial was registered at UMIN Clinical Trial Registry (number UMIN000026130). FINDINGS: All seven patients who met the inclusion criteria successfully achieved cell expansion, underwent intracerebral transplantation, and completed 1 year of follow-up. No product-related adverse events were observed. The median National Institutes of Health Stroke Scale and modified Rankin scale scores before transplantation were 13 and 4, which showed improvements of 1-8 and 0-2, respectively. Cell tracking proved that the engrafted cells migrated toward the infarction border area 1-6 months after transplantation, and the quantitative susceptibility mapping revealed that cell signals at the migrated area constantly increased throughout the follow-up period up to 34% of that of the initial transplanted site. CONCLUSIONS: Intracerebral transplantation of HUNS001-01 was safe and well tolerated. Cell tracking shed light on the therapeutic mechanisms of intracerebral transplantation. FUNDING: This work was supported by the Japan Agency for Medical Research and Development (AMED; JP17bk0104045 and JP20bk0104011).

Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p.

Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood-brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 µg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using 64Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p.

Ommaya reservoir placement using ultrasound guidance via anterior fontanelle combined with frameless electromagnetic neuronavigation in patients with mucopolysaccharidosis type 2: Case reports and review of the literature.

Mucopolysaccharidosis type II (MPS II) results from the genetic deficiency of a lysosomal enzyme and is associated with central nervous system (CNS) dysfunction. In Japan, in addition to intravenous enzyme administration, intracerebroventricular enzyme delivery through the Ommaya reservoir has recently gained approval. Nevertheless, the ideal approach for safely implanting the reservoir into the narrow ventricles of infantile MPS II patients remains uncertain. In this report, we present two cases of successful reservoir placement in infantile MPS II patients using ultrasound guidance via the anterior fontanelle, coupled with flameless electromagnetic neuronavigation.

Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

Use of Botulinum Toxin for Limb Immobilization for Rehabilitation in Rats with Experimental Stroke.

Motor rehabilitation strategies after unilateral stroke suggest that the immobilization of the healthy, unimpaired limb can promote the functional recovery of a paretic limb. In rodents, this has been modeled using casts, harnesses, and other means of restricting the use of the non-paretic forelimb in models of experimental stroke. Here, we evaluated an alternative approach, using botulinum toxin injections to limit the function of the non-paretic forelimb. Adult male rats were subjected to permanent ligation of the left distal middle cerebral artery, resulting in right forelimb paresis. The rats were then subjected to: (1) no treatment; (2) botulinum toxin injections 1 day post stroke; or (3) cast placement 5 days post stroke. Casts were removed after 5 weeks, while the botulinum toxin injection effectively immobilized subjects for approximately the same duration. Rats with bilateral forelimb impairment due to the stroke plus casting or botulinum injections were still able to feed and groom normally. Both immobilization groups showed modest recovery following the stroke compared to those that did not receive immobilization, but the casting approach led to unacceptable levels of animal stress. The botulinum toxin approach to limb immobilization had both advantages and disadvantages over traditional physical limb immobilization. The major advantage was that it was far less stress-inducing to the subject animals and appeared to be well tolerated. A disadvantage was that the paresis took roughly 10 weeks to fully resolve, and any degree of residual paresis could confound the interpretation of the behavioral assessments.

Stem Cell Therapies for Intracerebral Hemorrhage: Review of Preclinical and Clinical Studies.

Despite recent developments in the treatments for ischemic stroke, such as tissue plasminogen activator (t-PA) and thrombectomy, effective therapies for intracerebral hemorrhage (ICH) remain scarce. Stem cell therapies have attracted considerable attention owing to their potential neuro-regenerative ability; preclinical and clinical studies have been conducted to explore strategies for achieving functional recovery following ICH. In this review, we summarize the findings of preclinical studies on stem cell therapies of ICH, with a focus on different animal models, stem cell sources, transplantation methods, and their potential mechanisms of action. We also provide an overview of data from clinical trials to discuss the current status and future perspectives. Understanding the effectiveness and limitations of stem cell therapy and the future prospects could expand the applications of this novel therapeutic approach for ICH.

Impact of RNF213 c.14576G>A Variant on the Development of Direct and Indirect Revascularization in Pediatric Moyamoya Disease.

BACKGROUND: Superficial temporal artery (direct) and encephalomyosynangiosis (indirect) revascularization may develop after combined bypass surgery in pediatric patients with moyamoya disease (MMD). However, arterial development varies widely among patients, and the underlying mechanisms remain unknown. OBJECTIVES: We evaluated the relationship between the development of donor arteries after bypass surgery in pediatric patients with MMD and the MMD-susceptibility gene variant c.14576G>A of ring finger protein (RNF) 213. METHODS: The data of pediatric patients with MMD (age <16 years at the time of surgery) treated with combined bypass surgery between September 2013 and April 2019 were consecutively analyzed. Quantitative measurements of the superficial temporal artery (STA), deep temporal artery (DTA), and middle meningeal artery (MMA) diameters with magnetic resonance angiography (MRA) source imaging were performed preoperatively and at 6-12 months postoperatively. The postoperative caliber change ratios (CCRs) were calculated. The relationship between CCRs and RNF213 c.14576G>A status was examined. RESULTS: Forty-eight hemispheres from 28 pediatric patients with MMD were examined. Three hemispheres belonged to patients with the AA genotype; 33 to patients with the AG genotype (AA/AG group); and 12 to patients with the GG genotype (GG group; wild type). The CCRs for the DTA were significantly higher in patients with RNF213 variant (AA/AG group; 2.5 ± 0.1) than in the GG group (2.0 ± 0.2) (p = 0.03), whereas the CCRs for the STA were significantly higher in the GG (1.6 ± 0.1) than in the AA/AG group (1.3 ± 0.6) (p = 0.02). There was no significant difference in the CCRs for the MMA and basilar artery between the groups. Other factors, including sex, age, and MRA grading, were not associated with the development of specific bypass development. CONCLUSIONS: The extent of collateral development associated with direct or indirect bypass was found to differ between the genotypes of the RNF213 c.14576G>A associated with pediatric MMD. This genetic variant correlates with the development of the disease and affects revascularization after bypass surgery in pediatric patients with MMD.

Cell therapies for acute and chronic traumatic brain injury.

Traumatic brain injury (TBI) is a global health problem, for which there are no approved therapies. Advances in acute clinical care have improved post-TBI survival, yet many patients are left with chronic TBI-related disabilities (i.e. chronic TBI). Existing treatments that focus on rehabilitation and symptom management do not modify the disease and have limited effectiveness. Consequently, chronic TBI-related disabilities remain a significant unmet medical need. Cell therapies have neuroprotective and neurorestorative effects which are believed to modify the disease. In this article, we review the safety and efficacy of cell therapies in early-phase clinical studies that have shown potential to improve outcomes in acute to chronic phases of TBI.

Intracerebral Transplantation of Mesenchymal Stromal Cell Compounded with Recombinant Peptide Scaffold against Chronic Intracerebral Hemorrhage Model.

Background: Due to the lack of effective therapies, stem cell transplantation is an anticipated treatment for chronic intracerebral hemorrhage (ICH), and higher cell survival and engraftment are considered to be the key for recovery. Mesenchymal stromal cells (MSCs) compounded with recombinant human collagen type I scaffolds (CellSaics) have a higher potential for cell survival and engraftment compared with solo-MSCs, and we investigated the validity of intracerebral transplantation of CellSaic in a chronic ICH model. Methods: Rat CellSaics (rCellSaics) were produced by rat bone marrow-derived MSC (rBMSCs). The secretion potential of neurotrophic factors and the cell proliferation rate were compared under oxygen-glucose deprivation (OGD) conditions. rCellSaics, rBMSCs, or saline were transplanted into the hollow cavity of a rat chronic ICH model. Functional and histological analyses were evaluated, and single-photon emission computed tomography for benzodiazepine receptors was performed to monitor sequential changes in neuronal integrity. Furthermore, human CellSaics (hCellSaics) were transplanted into a chronic ICH model in immunodeficient rats. Antibodies neutralizing brain-derived neurotrophic factor (BDNF) were used to elucidate its mode of action. Results: rCellSaics demonstrated a higher secretion potential of trophic factors and showed better cell proliferation in the OGD condition. Animals receiving rCellSaics displayed better neurological recovery, higher intracerebral BDNF, and better cell engraftment; they also showed a tendency for less brain atrophy and higher benzodiazepine receptor preservation. hCellSaics also promoted significant functional recovery, which was reversed by BDNF neutralization. Conclusion: Intracerebral transplantation of CellSaics enabled neurological recovery in a chronic ICH model and may be a good option for clinical application.

Intravenous transplantation of amnion-derived mesenchymal stem cells promotes functional recovery and alleviates intestinal dysfunction after spinal cord injury.

Spinal cord injury (SCI) is often accompanied by gastrointestinal dysfunction due to the disconnection of the spinal autonomic nervous system. Gastrointestinal dysfunction reportedly upregulates intestinal permeability, leading to bacterial translocation of the gut microbiome to the systemic circulation, which further activates systemic inflammation, exacerbating neuronal damage. Mesenchymal stem cells (MSC) reportedly ameliorate SCI. Here, we aimed to investigate their effect on the associated gastrointestinal dysfunction. Human amnion-derived MSC (AMSCs) were intravenously transplanted one day after a rat model of midthoracic SCI. Biodistribution of transplanted cells, behavioral assessment, and histological evaluations of the spinal cord and intestine were conducted to elucidate the therapeutic effect of AMSCs. Bacterial translocation of the gut microbiome was examined by in situ hybridization and bacterial culture of the liver. Systemic inflammations were examined by blood cytokines, infiltrating immune cells in the spinal cord, and the size of the peripheral immune tissue. AMSCs released various neurotrophic factors and were mainly distributed in the liver and lung after transplantation. AMSC-transplanted animals showed smaller spinal damage and better neurological recovery with preserved neuronal tract. AMSCs transplantation ameliorated intestinal dysfunction both morphologically and functionally, which prevented translocation of the gut microbiome to the systemic circulation. Systemic inflammations were decreased in animals receiving AMSCs in the chronic phase. Intravenous AMSC administration during the acute phase of SCI rescues both spinal damage and intestinal dysfunction. Reducing bacterial translocation may contribute to decreasing systemic inflammation.

Outcomes of Combined Revascularization Surgery for Moyamoya Disease without Preoperative Cerebral Angiography.

OBJECTIVE: Cerebral angiography is the gold standard for diagnosing moyamoya disease (MMD), whereas magnetic resonance (MR) imaging/angiography is becoming more popular in the field of cerebrovascular disease due to its low invasiveness. Although there are concerns about using only MR imaging/angiography for preoperative analysis of MMD, considering the underestimation of pre-existing transdural collateral circulations and dangerous collaterals related to the risk of hemorrhage, we retrospectively reviewed our 10-year experience of MR imaging-first diagnosis and analyzed the perioperative outcomes. METHODS: We analyzed 160 consecutive direct/indirect combined revascularization procedures for MMD preoperatively assessed using MR imaging/angiography alone. Perioperative complications were assessed for up to 2 weeks after surgery. Locations of the lesions responsible for complications were further classified into the surgical field, the ipsilateral hemisphere outside the surgical field, and the contralateral hemisphere. RESULTS: Sixty-four revascularization procedures were performed in 38 children, and 96 procedures were performed in 68 adults. There was no difference in the incidence of perioperative ischemic complications between adults (6.3%) and pediatric patients (4.7%), but hemorrhagic complications were more frequently observed in adults (7.3%) than in children (0%) (P < 0.05). There was no specific lesion deviation for ischemic complications; however, hemorrhagic complications predominantly occurred in the surgical field. CONCLUSIONS: Direct/indirect combined revascularization surgery based on our preoperative diagnostic protocol with the MR-first strategy resulted in favorable outcomes in pediatric MMD patients with relatively low complication rates. However, the validity of the MR-first diagnostic protocol should be further evaluated in adult patients with MMD.

Impact of RNF213 founder polymorphism (p.R4810K) on the postoperative development of indirect pial synangiosis after direct/indirect combined revascularization surgery for adult Moyamoya disease.

Direct superficial temporal artery (STA) to middle cerebral artery (MCA) anastomosis combined with indirect pial synangiosis provides favorable surgical collaterals for Moyamoya disease (MMD), especially in adults; however, factors leading to the development of each direct and indirect collateral are not well documented.We aimed to investigate the association between RNF213 founder polymorphism (p.R4810K) and each direct and indirect collateral development. By qualitative and quantitative evaluations of direct and indirect surgical collaterals using time-of-flight MR angiography, postoperative development of each type of bypass was evaluated independently into two categories. Multivariate logistic regression analysis was performed to study the contributing factors for the development of each surgical collateral. Excellent development of postoperative direct and indirect bypass was observed in 65 hemispheres (70%) by qualitative evaluation, which was confirmed by quantitative evaluation. Multivariate logistic regression analysis of excellent indirect bypass development revealed a significant positive correlation with the p.R4810K (odds ratio, OR4.0; 95%-confidence interval, CI 1.2-16), advanced MR angiographic stage (OR9.5; 95%CI 1.7-73), and preoperative middle meningeal artery caliber (OR6.8; 95%CI 1.8-35), but a significant negative correlation was found with the excellent direct bypass development (OR0.17; 95%CI 0.03-0.75). No significant correlation was observed between excellent direct bypass development and the p.R4810K (OR0.95; 95%CI 0.37-2.4).In conclusion, excellent development of indirect collaterals after STA-MCA anastomosis combined with indirect pial synangiosis occurs more frequently in adult MMD with the RNF213 founder polymorphism, suggesting a role of the p.R4810K variant for marked in-growth of indirect collaterals and the utility of preoperative genetic analysis.

Induction of large cerebral aneurysms by intraperitoneal administration of ß-aminopropionitrile fumarate in male rats.

BACKGROUND: It is necessary and useful to obtain an experimental model which steadily and rapidly induces aneurysms for investigation of the pathogenesis of cerebral aneurysm. We attempted to examine whether intraperitoneal administration of ß-aminopropionitrile fumarate (BAPN-F) with additional treatments of induced hypertension and hemodynamic stress could steadily and rapidly induce aneurysms in male rats. METHODS: Seven-week-old male Sprague-Dawley rats pretreated with ligation of left common carotid and bilateral posterior renal arteries were administrated BAPN-F intraperitoneally. Induction rate and size of aneurysms was investigated with varying dose and duration of BAPN-F administration (low dose; 400 mg/kg/week for 4 or 8 weeks and high dose; 2800 mg/kg/week for 8 or 12 weeks). RESULTS: Induction rate in the high-dose groups was significantly higher (P<0.01) than that in the low-dose groups. Making comparisons between 8 and 12 weeks of the high-dose groups, while there was no difference in induction rate (8 weeks; 85.2% vs. 12 weeks; 76.9%), aneurysmal size was larger in 12 weeks (8 weeks; 127.5 µm, vs. 12 weeks; 181.7 µm in terms of median) but lethal intrathoracic hemorrhage was increased in 12 weeks (8 weeks; 7.4% vs. 12 weeks; 30.8%). Induction rate of large aneurysm was 22.2% and 30.8% in 8 and 12 weeks of the high-dose groups, respectively. CONCLUSIONS: High-dose BAPN-F administration can cause high-frequency aneurysmal induction. Although there was the difference in size and mortality rate based on administration duration, intraperitoneal administration of 2800 mg/kg/week BAPN-F for 8 weeks would be suitable for aneurysmal induction.

Mesenchymal Stem Cell Sheet Promotes Functional Recovery and Palliates Neuropathic Pain in a Subacute Spinal Cord Injury Model.

Stem cell therapy has been shown to reverse the sequelae of spinal cord injury (SCI). Although the ideal treatment route remains unknown, providing a large number of stem cells to the injured site using less invasive techniques is critical to achieving maximal recovery. This study was conducted to determine whether administration of bone marrow stem cell (BMSC) sheet made on its own without a scaffold is superior to intramedullary cell transplantation in a rat subacute SCI model. Adult female Sprague-Dawley rats were subjected to SCI by 30 g clip compression at the level of Th6 and Th7 and were administered BMSC cell sheet (7 × 104 cells, subdural), cell suspension (7 × 104 cells, intramedullary), or control seven days after the injury. Motor and sensory assessments, as well as histological evaluation, were performed to determine the efficacy of the different cell transplantation procedures. While both the cell sheet and cell intramedullary injection groups showed significant motor recovery compared to the control group, the cell sheet group showed better results. Furthermore, the cell sheet group displayed a significant sensory recovery compared to the other groups. A histological evaluation revealed that the cell sheet group showed smaller injury lesion volume, less inflammation, and gliosis compared to other groups. Sensory-related fibers of µ-opioid receptors (MOR, interneuron) and hydroxytryptamine transporters (HTT, descending pain inhibitory pathway), located around the dorsal horn of the spinal cord at the caudal side of the SCI, were preserved only in the cell sheet group. Stem cells could also be found inside the peri-injured spinal cord in the cell sheet group. BMSC cell sheets were able to promote functional recovery and palliate neuropathic pain more effectively than intramedullary injections, thus serving as a good treatment option for SCI.

Corrigendum to "Evaluation of Novel Stereotactic Cannula for Stem Cell Transplantation against Central Nervous System Disease".

[This corrects the article DOI: 10.1155/2020/4085617.].

Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial.

OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623). METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15). RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25). CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Identification of plaque location using intraoperative indocyanine green during carotid endarterectomy for patient with near occlusion.

BACKGROUND: Microscope-integrated near-infrared indocyanine green (ICG) videoangiography (VA) is an effective method of intraoperative blood-flow assessment and identification of plaque location during carotid endarterectomy (CEA). However, the validity of ICG-VA during CEA for patient with near occlusion has not been elucidated. METHODS: Thirty-four CEA procedures were performed between June 2009 and December 2017 for patient with near occlusion, which are more than 95% stenosis. The lesions were classified into three groups according to the diameter of distal ICA compared with ipsilateral external carotid artery (ECA), as normal diameter (>100%), moderate diameter reduction (50-100%), severe diameter reduction (<50%). Five mg of ICG was injected intravenously before arteriotomy, and ICG-VA was taken to identify the distal end of the plaque. Depiction of the distal end and its accuracy were retrospectively reviewed. RESULTS: There were 18 cases with normal diameter group, 14 cases with moderate diameter reduction group, and 2 cases with severe diameter reduction group. All but one case in the severe diameter reduction group showed apparent distal end signal which were confirmed by arteriotomy afterward. CONCLUSIONS: The present study clearly denotes that ICG-VA can visualize the carotid plaque distal end during the CEA, even with the patient with near occlusion. However, it should be noted that there may be a difficulty in visualization of the distal plaque end for patient with severely collapsed distal ICA.

The validity of the acute stroke assessment using rapid pseudo-continuous arterial spin labeling (ASAP-ASL) method for acute thrombectomy.

BACKGROUND: Recent clinical trials demonstrated the efficacy of thrombectomy for ischemic stroke against acute large vessel occlusion (LVO). To overcome the problem with excessive examination time for diagnosis of cerebral perfusion and/or the use of contrast agent to determine penumbra, we adopted a new magnetic resonance imaging technique named Acute Stroke Assessment using rapid Pseudo-continuous arterial spin labeling (ASAP-ASL) method. METHODS: The study included healthy volunteers and clinical patients. The signal to noise ratio (SNR) and acquisition time were compared with various numbers of signal average (NSA) of rapid pseudo-continuous arterial spin labeling (pCASL) using the 10-mm thick slice width and narrow scan range focusing the level of basal ganglia by healthy volunteers. After applying clinically acceptable protocol for ASAP-ASL, we then checked image qualities and an accuracy of the method by comparing with the angiographical imaging obtained from the clinical patients regarding the degree of consistency. RESULTS: NSA were compared between two and fourteen, and 10 NSA was decided to be introduced for clinical use (1 minutes and 17 second) for obtaining clinically acceptable image, which was shorter than the time required for ordinary whole brain pCASL (approximately 5 minutes). In the clinical study, the occlusion site estimated by ASAP-ASL showed high correlation with that of digital subtraction angiography (κ=0.63-0.79). CONCLUSIONS: ASAP-ASL method requires approximately one minutes to obtain clinically relevant brain perfusion imaging which can successfully identify ischemic region in LVO patients.

Long-Term Clinical Outcome and Prognosis After Thrombectomy in Patients With Concomitant Malignancy.

Endovascular thrombectomy (EVT) is the preferred treatment strategy for patients with acute ischemic stroke (AIS). However, clinical outcome and prognosis in patients who undergo EVT in response to AIS with concomitant malignancy have not been fully elucidated. Data of patients with malignancy who underwent EVT at participating institutions between January 2015 and April 2019 were retrospectively analyzed. Patient characteristics, treatment methods, posttreatment strategy, and long-term prognosis were evaluated in 12 patients with prediagnoses of malignancy. Good revascularization (TICI 2b or higher) was achieved in 10 of 12 patients. Among the eight patients who survived more than 2 weeks from onset, four patients showed good clinical outcome [modified Rankin Scale (mRS) <2] at 60 days posttreatment and were able to continue treatment for malignancy. However, seven of eight patients died within a year of EVT (median survival, 83 days) due to progression of malignancy. One-year survival was achieved in only one patient whose etiology of stroke was determined as infectious endocarditis and not Trousseau syndrome. Even after successful revascularization and good short-term clinical outcome, the long-term prognosis after thrombectomy in patients with malignancy was poor. Thrombectomy for concomitant malignancy requires judicious decision, and further studies are necessary to fully elucidate its efficacy.