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PURPOSE OF REVIEW: Glioblastoma remains resistant to most conventional treatments. Despite scientific advances in the past three decades, there has been a dearth of effective new treatments. New approaches to drug delivery and clinical trial design are needed. RECENT FINDINGS: We discuss how the blood-brain barrier and tumor microenvironment pose challenges for development of effective therapies for glioblastoma. Next, we discuss treatments in development that aim to overcome these barriers, including novel drug designs such as nanoparticles and antibody-drug conjugates, novel methods of drug delivery, including convection-enhanced and intra-arterial delivery, and novel methods to enhance drug penetration, such as blood-brain barrier disruption by focused ultrasound and laser interstitial thermal therapy. Lastly, we address future opportunities, positing combination therapy as the best strategy for effective treatment, neoadjuvant and window-of-opportunity approaches to simultaneously enhance therapeutic effectiveness with interrogation of on-treatment biologic endpoints, and adaptive platform and basket trials as imperative for future trial design. New approaches to GBM treatment should account for the blood-brain barrier and immunosuppression by improving drug delivery, combining treatments, and integrating novel clinical trial designs.
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Antineoplásicos , Neoplasias Encefálicas , Glioblastoma , Humanos , Barreira Hematoencefálica/patologia , Glioblastoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Microambiente TumoralRESUMO
BACKGROUND: Prophylactic carotid artery stenting (CAS) is an effective strategy to reduce perioperative stroke in patients with severe carotid stenosis who require cardiothoracic surgery (CTS). Staging both procedures (CAS-CTS) during a single hospitalization presents conflicting demands for antiplatelet therapy and the optimal pharmacologic strategy between procedures is not established. The purpose of this study is to present our initial experience with a "bridging" protocol for staged CAS-CTS. METHODS: A retrospective review of staged CAS-CTS procedures at a single referral center was performed. All patients had multivessel coronary and/or valvular disease and severe carotid stenosis (>70%). Patients not previously on aspirin were also started on aspirin prior to surgery, followed by eptifibatide during CAS (intraprocedural bolus followed by post-procedural infusion which was continued until the morning of surgery). Pre- and perioperative (30 days) neurologic morbidity and mortality was the primary endpoint. RESULTS: 11 CAS procedures were performed in 10 patients using the protocol. The median duration of eptifibatide bridge therapy was 36 h (range 24-288 h). There was one minor bleeding complication (1/11, 9.1%) and no major bleeding complications during the bridging and post-operative period. There was one post-operative, non-neurologic death and zero perioperative ischemic strokes. CONCLUSIONS: For patients undergoing staged CAS-CTS, Eptifibatide bridging therapy is a viable temporary antiplatelet strategy with a favorable safety profile. This strategy enables a flexible range of time-intervals between procedures.
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Background For patients with acute ischemic stroke undergoing endovascular mechanical thrombectomy with x-ray angiography, the use of adjuncts to maintain vessel patency, such as stents or antiplatelet medications, can increase risk of periprocedural complications. Criteria for using these adjuncts are not well defined. Purpose To evaluate use of MRI to guide critical decision making by using a combined biplane x-ray neuroangiography 3.0-T MRI suite during acute ischemic stroke intervention. Materials and Methods This retrospective observational study evaluated consecutive patients undergoing endovascular intervention for acute ischemic stroke between July 2019 and May 2020 who underwent either angiography with MRI or angiography alone. Cerebral tissue viability was assessed by using MRI as the reference standard. For statistical analysis, Fisher exact test and Student t test were used to compare groups. Results Of 47 patients undergoing acute stroke intervention, 12 patients (median age, 69 years; interquartile range, 60-77 years; nine men) underwent x-ray angiography with MRI whereas the remaining 35 patients (median age, 80 years; interquartile range, 68-86 years; 22 men) underwent angiography alone. MRI results influenced clinical decision making in one of three ways: whether or not to perform initial or additional mechanical thrombectomy, whether or not to place an intracranial stent, and administration of antithrombotic or blood pressure medications. In this initial experience, decision making during endovascular acute stroke intervention in the combined angiography-MRI suite was better informed at MRI, such that therapy was guided in real time by the viability of the at-risk cerebral tissue. Conclusion Integrating intraprocedural 3.0-T MRI into acute ischemic stroke treatment was feasible and guided decisions of whether or not to continue thrombectomy, to place stents, or to administer antithrombotic medication or provide blood pressure medications. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Lev and Leslie-Mazwi in this issue.
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Angiografia Cerebral/métodos , Tomada de Decisões , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/cirurgia , Imageamento por Ressonância Magnética/métodos , Acidente Vascular Cerebral/diagnóstico por imagem , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Idoso , Feminino , Humanos , Recém-Nascido , Período Intraoperatório , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Dural arteriovenous fistulas (DAVFs) are high-flow acquired shunts that can carry high risk of intracranial hemorrhage. Because DAVFs can often be managed by endovascular means, early and accurate diagnosis can markedly improve patient morbidity. Time-of-flight and arterial spin-labeling MRA have increased the diagnostic utility of MRI for DAVF by showing hemodynamic rather than anatomic evidence of shunting. The purpose of this article is to describe the cases of seven patients who had co-localization of arterial spin-labeling signal intensity and time-of-flight flow-related enhancement in the left skull base, resulting in a misdiagnosis of DAVF and a recommendation for catheter angiography by the interpreting radiologist. Benign jugular venous reflux is identified as a common mechanism in each case, and the physiology behind this imaging pitfall is described. An algorithmic diagnostic approach to differentiating physiologic venous reflux from true posterior skull base DAVFs is presented.
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Malformações Vasculares do Sistema Nervoso Central/diagnóstico por imagem , Veias Jugulares/diagnóstico por imagem , Veias Jugulares/fisiopatologia , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Malformações Vasculares do Sistema Nervoso Central/fisiopatologia , Diagnóstico Diferencial , Feminino , Humanos , Angiografia por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Particulate emboli are passive agents that follow blood flow. Deployed antireflux devices obstruct blood flow. CONCLUSION: The aim of this review is to describe the complex hemodynamic alterations to blood flow caused by the deployment of antireflux devices and the resulting changes to embolic distribution. The therapeutic goal is optimization of embolization safety and efficacy.
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Embolização Terapêutica/instrumentação , Angiografia , Embolectomia com Balão , Desenho de Equipamento , Hemodinâmica , Humanos , Dispositivos de Acesso VascularRESUMO
Purpose To determine if high lung shunt fraction (LSF) is an independent prognostic indicator of poor survival in patients who undergo yttrium 90 radioembolization for unresectable liver-dominant metastatic colorectal cancer. Materials and Methods Retrospective data were analyzed from 606 patients (62% men; mean age, 62 years) who underwent radioembolization to treat liver metastases from colorectal adenocarcinoma between July 2002 and December 2011 at 11 U.S. centers. Institutional review board exemptions were granted prior to the collection of data at each site. Overall survival was estimated by using Kaplan-Meier survival and univariate Cox proportional hazards models to examine the effect of LSF on survival and to compare this to other potential prognostic indicators. Multivariate analysis was also performed to determine whether LSF is an independent risk factor for poor survival. Results LSF higher than 10% was predictive of significantly decreased survival (median, 6.9 months vs 10.0 months; hazard ratio, 1.60; P < .001) and demonstrated a mild but significant correlation to serum carcinoembryonic antigen levels and tumor-to-liver volume ratio (Pearson correlation coefficients, 0.105 and 0.113, respectively; P < .05). A progressive decrease in survival was observed as LSF increased from less than 5% to more than 20% (P < .05). LSF did not correlate with the presence of extrahepatic metastases or prior administration of bevacizumab. Conclusion Increased LSF is an independent prognostic indicator of worse survival in patients undergoing radioembolization for liver-dominant metastatic colorectal adenocarcinoma. High LSF correlates poorly to other potential markers of tumor size, such as tumor-to-liver volume ratio or serum carcinoembryonic antigen level, and does not correlate to the presence of extrahepatic metastases. © RSNA, 2016 Online supplemental material is available for this article.
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Adenocarcinoma/radioterapia , Fístula Arteriovenosa/complicações , Neoplasias Colorretais/radioterapia , Embolização Terapêutica/métodos , Radioisótopos de Ítrio/uso terapêutico , Adenocarcinoma/diagnóstico por imagem , Adenocarcinoma/patologia , Adulto , Idoso , Angiografia , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/patologia , Feminino , Humanos , Fígado/irrigação sanguínea , Pulmão/irrigação sanguínea , Imageamento por Ressonância Magnética , Masculino , Microesferas , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Fluorine-19 magnetic resonance imaging ((19)F MRI) probes enable quantitative in vivo detection of cell therapies and inflammatory cells. Here, we describe the formulation of perfluorocarbon-based nanoemulsions with improved sensitivity for cellular MRI. Reduction of the (19)F spin-lattice relaxation time (T1) enables rapid imaging and an improved signal-to-noise ratio, thereby improving cell detection sensitivity. We synthesized metal-binding ß-diketones conjugated to linear perfluoropolyether (PFPE), formulated these fluorinated ligands as aqueous nanoemulsions, and then metallated them with various transition and lanthanide ions in the fluorous phase. Iron(III) tris-ß-diketonate ('FETRIS') nanoemulsions with PFPE have low cytotoxicity (<20%) and superior MRI properties. Moreover, the (19)F T1 can readily be reduced by an order of magnitude and tuned by stoichiometric modulation of the iron concentration. The resulting (19)F MRI detection sensitivity is enhanced by three- to fivefold over previously used tracers at 11.7 T, and is predicted to increase by at least eightfold at the clinical field strength of 3 T.
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Compostos Férricos/química , Imagem por Ressonância Magnética de Flúor-19/métodos , Fluorocarbonos/química , Animais , Linhagem Celular Tumoral , Camundongos , Ratos , Sensibilidade e EspecificidadeRESUMO
PURPOSE: To assess whether blood pressure changes in the downstream vascular compartment are greater with transarterial chemoembolization than transarterial radioembolization (TARE) when using an anti-reflux catheter. MATERIALS AND METHODS: The Surefire Infusion System (Surefire Medical, Inc, Westminster, Colorado) was used for lobar and sublobar administration in 51 drug-eluting embolic transarterial chemoembolization and 55 TARE procedures (22 with resin microspheres [TARE/resin] and 33 with glass microspheres [TARE/glass]). Of patients receiving transarterial chemoembolization and TARE/glass, 97% had hepatocellular carcinomas; 87% of patients receiving TARE/resin had metastases. The absolute (mm Hg) and relative (%) changes in the systemic-hepatic arterial pressure difference (SHAPD) were calculated from simultaneous blood pressure measurements obtained from the femoral artery vascular sheath and the antireflux catheter before, after, and, when feasible, during transarterial chemoembolization or TARE. RESULTS: Transarterial chemoembolization was associated with a significant reduction in SHAPD compared with TARE (13 mm Hg ± 1.7 vs -4.3 mm Hg ± 1.5; P < .001). A reduction in SHAPD led to early termination of 55.6% of lobar and 53.3% of sublobar transarterial chemoembolization procedures compared with only 5.5% of lobar TARE/resin and no TARE/glass procedures. TARE/resin procedures were associated with a significantly greater change in SHAPD compared with TARE/glass procedures (0.9 mm Hg ± 2.7 vs -8.0 mm Hg ± 1.5; P = .0035). CONCLUSIONS: Hepatic arterial pressures in the treated vascular compartment increased more after transarterial chemoembolization than after TARE, suggesting that transarterial chemoembolization resulted in more embolic obstruction of the targeted vascular compartment than TARE.
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Pressão Arterial , Determinação da Pressão Arterial/instrumentação , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/instrumentação , Embolização Terapêutica/instrumentação , Artéria Hepática/fisiopatologia , Neoplasias Hepáticas/terapia , Compostos Radiofarmacêuticos/administração & dosagem , Dispositivos de Acesso Vascular , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Embolização Terapêutica/efeitos adversos , Embolização Terapêutica/métodos , Desenho de Equipamento , Feminino , Vidro , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/patologia , Masculino , Microesferas , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/efeitos adversos , Resinas Sintéticas , Estudos Retrospectivos , Fatores de Tempo , Resultado do TratamentoRESUMO
PURPOSE: To assess whether intravascular ultrasound (US) guidance impacts number of needle passes, contrast usage, radiation dose, and procedure time during creation of transjugular intrahepatic portosystemic shunts (TIPS). MATERIALS AND METHODS: Intravascular US-guided creation of TIPS in 40 patients was retrospectively compared with conventional TIPS in 49 patients between February 2010 and November 2015 at a single tertiary care institution. Patient sex and age, etiology of liver disease (hepatitis C virus, alcohol abuse, nonalcoholic steatohepatitis), severity of liver disease (mean Model for End-Stage Liver Disease score), and indications for TIPS (variceal bleeding, refractory ascites, refractory hydrothorax) in conventional and intravascular US-guided cases were recorded. RESULTS: The two groups were well matched by sex, age, etiology of liver disease, Child-Pugh class, Model for End-Stage Liver Disease scores, and indication for TIPS (P range = .19-.94). Fewer intrahepatic needle passes were required in intravascular US-guided TIPS creation compared with conventional TIPS (2 passes vs 6 passes, P < .01). Less iodinated contrast material was used in intravascular US cases (57 mL vs 140 mL, P < .01). Radiation exposure, as measured by cumulative dose, dose area product, and fluoroscopy time, was reduced with intravascular US (174 mGy vs 981 mGy, P < .01; 3,793 µGy * m(2) vs 21,414 µGy * m(2), P < .01; 19 min vs 34 min, P < .01). Procedure time was shortened with intravascular US (86 min vs 125 min, P < .01). CONCLUSIONS: Intravascular US guidance resulted in fewer intrahepatic needle passes, decreased contrast medium usage, decreased radiation dosage, and shortened procedure time in TIPS creation.
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Hipertensão Portal/cirurgia , Veia Porta/cirurgia , Derivação Portossistêmica Transjugular Intra-Hepática , Doses de Radiação , Radiografia Intervencionista , Ultrassonografia de Intervenção , Adulto , Idoso , California , Meios de Contraste/administração & dosagem , Fluoroscopia , Humanos , Hipertensão Portal/diagnóstico por imagem , Hipertensão Portal/etiologia , Hipertensão Portal/fisiopatologia , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico , Pessoa de Meia-Idade , Agulhas , Duração da Cirurgia , Pressão na Veia Porta , Veia Porta/diagnóstico por imagem , Veia Porta/fisiopatologia , Derivação Portossistêmica Transjugular Intra-Hepática/efeitos adversos , Derivação Portossistêmica Transjugular Intra-Hepática/instrumentação , Punções , Exposição à Radiação , Radiografia Intervencionista/efeitos adversos , Radiografia Intervencionista/métodos , Estudos Retrospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Ultrassonografia de Intervenção/efeitos adversosRESUMO
OBJECTIVE: The purpose of this study was to describe the technique for evaluating hepatic arterial blood pressure changes during lobar chemoembolization using antireflux devices. Intraprocedural femoral and hepatic arterial blood pressures were measured and chemoembolization terminated when significant reduction in the difference occurred. Liver toxicity was evaluated. Eleven patients underwent 24 lobar chemoembolization procedures. Early termination of delivery occurred in 11 of 24 (46%) procedures in which the mean relative reduction in systemic-hepatic arterial pressure differential was 48%. The mean liver toxicity score was 1.2. This compares to delivery of the entire dose in 13 of 24 (54%) procedures in which the mean relative reduction in systemic-hepatic arterial pressure differential was 12% with a mean liver toxicity score of 1.2. CONCLUSION: When antireflux devices are used, intraprocedural assessment of hepatic artery blood pressure changes may be a useful embolization safety endpoint.
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Antineoplásicos/administração & dosagem , Pressão Sanguínea , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/instrumentação , Artéria Femoral , Artéria Hepática , Neoplasias Hepáticas/terapia , Idoso , Idoso de 80 Anos ou mais , Angiografia Digital , Meios de Contraste , Doxorrubicina/administração & dosagem , Óleo Etiodado/administração & dosagem , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios X , Ácidos Tri-IodobenzoicosRESUMO
Poor cell survival severely limits the beneficial effects of stem cell therapy for peripheral arterial disease (PAD). This study was designed to investigate the role of mammalian target of rapamycin (mTOR) in the survival and therapeutic function of transplanted murine adipose-derived stromal cells (mADSCs) in a murine PAD model. mADSCs (1.0 × 10(7)) were isolated from dual-reporter firefly luciferase and enhanced green fluorescent protein-positive transgenic mice, intramuscularly implanted into the hind limb of C57BL/6 mice after femoral artery ligation/excision, and monitored using noninvasive bioluminescence imaging (BLI). Although engrafted mADSCs produced antiapoptotic/proangiogenic effects in vivo by modulating the inflammatory and angiogenic cytokine response involving the mTOR pathway, longitudinal BLI revealed progressive death of post-transplant mADSCs within ~4 weeks in the ischemic hind limb. Selectively targeting mTOR complex-1 (mTORC1) using low-dose rapamycin treatment with mADSCs attenuated proinflammatory cytokines (interleukin [IL]-1ß and tumor necrosis factor-alpha [TNF-α]) expression and neutrophil/macrophage infiltration, which overtly promoted mADSCs viability and antiapoptotic/proangiogenic efficacy in vivo. However, targeting dual mTORC1/mTORC2 using PP242 or high-dose rapamycin caused IL-1ß/TNF-α upregulation and anti-inflammatory IL-10, IL-6, and vascular endothelial growth factor/vascular endothelial growth factor receptor 2 downregulation, undermining the survival and antiapoptotic/proangiogenic action of mADSCs in vivo. Furthermore, low-dose rapamycin abrogated TNF-α secretion by mADSCs and rescued the cells from hypoxia/reoxygenation-induced death in vitro, while PP242 or high-dose rapamycin exerted proinflammatory effects and promoted cell death. In conclusion, mTORC1 and mTORC2 may differentially regulate inflammation and affect transplanted mADSCs' functional survival in ischemic hind limb. These findings uncover that mTOR may evolve into a promising candidate for mechanism-driven approaches to facilitate the translation of cell-based PAD therapy.
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Isquemia/metabolismo , Complexos Multiproteicos/metabolismo , Doença Arterial Periférica/metabolismo , Proteínas/metabolismo , Células Estromais/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Adipócitos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células , Sobrevivência Celular , Modelos Animais de Doenças , Regulação para Baixo , Artéria Femoral/cirurgia , Proteínas de Fluorescência Verde/genética , Membro Posterior/irrigação sanguínea , Membro Posterior/metabolismo , Inflamação/metabolismo , Interleucina-10/biossíntese , Interleucina-1beta/biossíntese , Interleucina-6/biossíntese , Isquemia/cirurgia , Luciferases de Vaga-Lume/genética , Medições Luminescentes , Macrófagos/imunologia , Alvo Mecanístico do Complexo 1 de Rapamicina , Alvo Mecanístico do Complexo 2 de Rapamicina , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neovascularização Patológica , Neutrófilos/imunologia , Doença Arterial Periférica/terapia , Sirolimo/farmacologia , Células Estromais/transplante , Fator de Necrose Tumoral alfa/biossíntese , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Regulação para Cima , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/biossíntese , Fatores de Crescimento do Endotélio Vascular/biossínteseRESUMO
BACKGROUND: Intracranial dural arteriovenous (AV) fistula classifications focus on presence/absence of retrograde flow in the cortical veins of the brain as this angiographic finding portends a worse prognosis. However, prior categorization systems of AV shunts in the spine do not incorporate these features. We propose an updated classification for spinal shunting lesions that terms any shunting lesion with retrograde flow in any cortical vein of the brain or spinal cord medullary vein as "high risk". To present this classification, we analyzed our center's most recent experience with cervical spine shunting lesions. METHODS: The electronic medical record at our institution was reviewed to identify shunting lesions of the cervical spine and patient demographics/presentation. Comprehensive craniospinal digital subtraction angiograms were evaluated to classify shunt location, type (arteriovenous malformation (AVM) vs arteriovenous fistula (AVF)), and presence of high-risk venous drainage. RESULTS: Some 52 lesions were identified and categorized as pial/dural/epidural/paravertebral AVFs and intramedullary/extraspinal AVMs. Lesions were classified as high risk or not depending on the presence of retrograde flow into at least one vein that directly drains the spinal cord or brain. All patients who presented with either hemorrhage or infarct had underlying high-risk lesions. Additionally, 50% (17/34) of symptomatic patients with high-risk lesions presented with neurological extremity symptoms (OR=10.0, p=0.037) most of which fit a myelopathic pattern. CONCLUSION: We present an updated classification system for shunting lesions of the spine that focuses on high-risk retrograde flow to the brain or spine in addition to anatomical location in order to better inform patient management.
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BACKGROUND: Early clinical trials validating endovascular therapy (EVT) for emergent large vessel occlusion (ELVO) ischemic stroke in the anterior circulation initially focused on patients with small or absent completed infarctions (ischemic cores) to maximize the probability of detecting a clinically meaningful and statistically significant benefit of EVT. Subsequently, real-world experience suggested that patients with large core ischemic strokes (LCS) at presentation may also benefit from EVT. Several large, retrospective, and prospective randomized clinical trials have recently been published that further validate this approach. These guidelines aim to provide an update for endovascular treatment of LCS. METHODS: A structured literature review of LCS studies available since 2019 and grading the strength and quality of the evidence was performed. Recommendations were made based on these new data by consensus of the authors, with additional input from the full SNIS Standards and Guidelines Committee and the SNIS Board of Directors. RESULTS: The management of ELVO strokes with large ischemic cores continues to evolve. The expert panel agreed on several recommendations: Recommendation 1: In patients with anterior circulation ELVO who present within 24 hours of last known normal with large infarct core (70-149 mL or ASPECTS 3-5) and meet other criteria of RESCUE-Japan LIMIT, SELECT2, ANGEL-ASPECT, TESLA, TENSION, or LASTE trials, thrombectomy is indicated (Class I, Level A). Recommendations 2-7 flow directly from recommendation 1. Recommendation 2: EVT in patients with LCS aged 18-85 years is beneficial (Class I, Level A). Recommendation 3: EVT in patients with LCS >85 years of age may be beneficial (Class I, Level B-R). Recommendation 4: Patients with LCS and NIHSS score 6-30 benefit from EVT in LCS (Class I, Level A). Recommendation 5: Patients with LCS and NIHSS score <6 and >30 may benefit from EVT in LCS (Class IIa, Level A). Recommendation 6: Patients with LCS and low baseline mRS (0-1) benefit from EVT (Class I, Level A). Recommendation 7: Patients with LCS and time of last known well 0-24 hours benefit from EVT (Class I, Level A). Recommendation 8: It is recommended that patients with ELVO LCS who also meet the criteria for on-label or guideline-directed use of IV thrombolysis receive IV thrombolysis, irrespective of whether endovascular treatments are being considered (Class I, Level B-NR). CONCLUSIONS: The indications for endovascular treatment of ELVO strokes continue to expand and now include patients with large ischemic cores on presentation. Further prospective randomized studies, including follow-up to assess the population-based efficacy of treating patients with LCS, are warranted.
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BACKGROUND: Human cardiac progenitor cells (hCPCs) are a promising cell source for regenerative repair after myocardial infarction. Exploitation of their full therapeutic potential may require stable genetic modification of the cells ex vivo. Safe genetic engineering of stem cells, using facile methods for site-specific integration of transgenes into known genomic contexts, would significantly enhance the overall safety and efficacy of cellular therapy in a variety of clinical contexts. METHODS AND RESULTS: We used the phiC31 site-specific recombinase to achieve targeted integration of a triple fusion reporter gene into a known chromosomal context in hCPCs and human endothelial cells. Stable expression of the reporter gene from its unique chromosomal integration site resulted in no discernible genomic instability or adverse changes in cell phenotype. Namely, phiC31-modified hCPCs were unchanged in their differentiation propensity, cellular proliferative rate, and global gene expression profile when compared with unaltered control hCPCs. Expression of the triple fusion reporter gene enabled multimodal assessment of cell fate in vitro and in vivo using fluorescence microscopy, bioluminescence imaging, and positron emission tomography. Intramyocardial transplantation of genetically modified hCPCs resulted in significant improvement in myocardial function 2 weeks after cell delivery, as assessed by echocardiography (P=0.002) and MRI (P=0.001). We also demonstrated the feasibility and therapeutic efficacy of genetically modifying differentiated human endothelial cells, which enhanced hind limb perfusion (P<0.05 at day 7 and 14 after transplantation) on laser Doppler imaging. CONCLUSIONS: The phiC31 integrase genomic modification system is a safe, efficient tool to enable site-specific integration of reporter transgenes in progenitor and differentiated cell types.
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Células-Tronco Fetais/transplante , Terapia Genética/métodos , Membro Posterior/irrigação sanguínea , Isquemia/cirurgia , Mutagênese Insercional/métodos , Infarto do Miocárdio/cirurgia , Animais , Diferenciação Celular , Divisão Celular , Cromossomos Humanos Par 19/genética , Células Endoteliais/citologia , Feminino , Coração Fetal/citologia , Células-Tronco Fetais/citologia , Células-Tronco Fetais/metabolismo , Regulação da Expressão Gênica , Genes Reporter , Humanos , Integrases , Peptídeos e Proteínas de Sinalização Intracelular , Isquemia/fisiopatologia , Luciferases de Vaga-Lume/genética , Proteínas Luminescentes/genética , Imageamento por Ressonância Magnética , Camundongos , Camundongos SCID , Proteínas/genética , Distribuição Aleatória , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/genética , Timidina Quinase/genética , Transgenes , Proteínas de Transporte Vesicular , Proteínas Virais/genética , Integração Viral , Proteína Vermelha FluorescenteRESUMO
The successful derivation of human induced pluripotent stem cells (hiPSCs) by dedifferentiation of somatic cells offers significant potential to overcome obstacles in the field of cardiovascular disease. hiPSC derivatives offer incredible potential for new disease models and regenerative medicine therapies. However, many questions remain regarding the optimal starting materials and methods to enable safe, efficient derivation of hiPSCs suitable for clinical applications. Initial reprogramming experiments were carried out using lentiviral or retroviral gene delivery methods. More recently, various nonviral methods that avoid permanent and random transgene insertion have emerged as alternatives. These include transient DNA transfection using plasmids or minicircles, protein transduction, or RNA transfection. In addition, several small molecules have been found to significantly augment hiPSC derivation efficiency, allowing the use of a fewer number of genes during pluripotency induction. We review these various methods for the derivation of hiPSCs, focusing on their ultimate clinical applicability, with an emphasis on their potential for use as cardiovascular therapies and disease-modeling platforms.
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Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Desdiferenciação Celular/fisiologia , Miócitos Cardíacos/citologia , Células-Tronco Pluripotentes/citologia , Humanos , Miócitos Cardíacos/fisiologia , Células-Tronco Pluripotentes/fisiologiaRESUMO
OBJECTIVE: Clinical trials of bone marrow-derived stem cell therapy for the heart have yielded variable results. The basic mechanism(s) that underlies their potential efficacy remains unknown. In the present study, we evaluated the survival kinetics, transcriptional response, and functional outcome of intramyocardial bone marrow mononuclear cell (BMMC) transplantation for cardiac repair in a murine myocardial infarction model. METHODS AND RESULTS: We used bioluminescence imaging and high-throughput transcriptional profiling to evaluate the in vivo survival kinetics and gene expression changes of transplanted BMMCs after their engraftment into ischemic myocardium. Our results demonstrate short-lived survival of cells following transplant, with less than 1% of cells surviving by 6 weeks posttransplantation. Moreover, transcriptomic analysis of BMMCs revealed nonspecific upregulation of various cell regulatory genes, with a marked downregulation of cell differentiation and maturation pathways. BMMC therapy caused limited improvement of heart function as assessed by echocardiography, invasive hemodynamics, and positron emission tomography. Histological evaluation of cell fate further confirmed findings of the in vivo cell tracking and transcriptomic analysis. CONCLUSIONS: Collectively, these data suggest that BMMC therapy, in its present iteration, may be less efficacious than once thought. Additional refinement of existing cell delivery protocols should be considered to induce better therapeutic efficacy.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Isquemia Miocárdica/terapia , Animais , Sobrevivência Celular , Ecocardiografia , Feminino , Perfilação da Expressão Gênica , Genes Reporter , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Isquemia Miocárdica/genética , Isquemia Miocárdica/patologia , Isquemia Miocárdica/fisiopatologia , Tomografia por Emissão de Pósitrons , Fatores de TempoRESUMO
BACKGROUND: Pulsatile tinnitus (PT) can cause significant detriment to quality of life and may herald a life-threatening condition. Endovascular evaluation is the gold standard for the definitive diagnosis of PT and facilitates treatment. However, no large study has determined the distribution of causes and treatment outcomes of PT evaluated endovascularly. METHODS: Consecutive patients evaluated at a multidisciplinary PT clinic from a single academic center were retrospectively reviewed. Patients with a suspected cerebrovascular etiology of PT based on clinical and/or non-invasive imaging, who were evaluated by endovascular techniques (arteriography, venography, manometry, and/or balloon test occlusion), were included in analysis. Baseline clinical features and treatment results by final etiology of PT were compared. RESULTS: Of 552 patients referred for PT evaluation, 164 patients (29.7%) who underwent endovascular evaluation of PT were included. Mean (±SD) age at first clinical evaluation was 54.3±14.1 years (range 25-89 years); 111 patients (67.7%) were female. PT causes were 75.6% vascular and 24.4% non-vascular. Arteriovenous shunting lesions caused 20.7% of cases, venous etiologies 48.2%, and arterial etiologies 6.7%. Of patients with a shunting lesion treated with endovascular embolization, 96.9% had lasting significant improvement or resolution in PT. Endovascular stenting for venous sinus stenosis gave 84.6% of patients lasting improvement or resolution in PT. Arterial and non-vascular PT had fewer patients treated endovascularly and less improvement in PT symptoms. CONCLUSION: PT with a suspected vascular cause is most often attributable to venous etiologies. PT caused by arteriovenous shunting or venous sinus stenosis may be effectively treated endovascularly.
Assuntos
Zumbido , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Masculino , Zumbido/diagnóstico por imagem , Zumbido/etiologia , Zumbido/terapia , Constrição Patológica/complicações , Estudos Retrospectivos , Qualidade de Vida , Cavidades CranianasRESUMO
BACKGROUND: Pulsatile tinnitus (PT) may be due to a spectrum of cerebrovascular etiologies, ranging from benign venous turbulence to life threatening dural arteriovenous fistulas. A focused clinical history and physical examination provide clues to the ultimate diagnosis; however, the predictive accuracy of these features in determining PT etiology remains uncertain. METHODS: Patients with clinical PT evaluation and DSA were included. The final etiology of PT after DSA was categorized as shunting, venous, arterial, or non-vascular. Clinical variables were compared between etiologies using multivariate logistic regression, and performance at predicting PT etiology was determined by area under the receiver operating curve (AUROC). RESULTS: 164 patients were included. On multivariate analysis, patient reported high pitch PT (relative risk (RR) 33.81; 95% CI 3.81 to 882.80) compared with exclusively low pitch PT and presence of a bruit on physical examination (9.95; 2.04 to 62.08; P=0.007) were associated with shunting PT. Hearing loss was associated with a lower risk of shunting PT (0.16; 0.03 to 0.79; P=0.029). Alleviation of PT with ipsilateral lateral neck pressure was associated with a higher risk of venous PT (5.24; 1.62 to 21.01; P=0.010). An AUROC of 0.882 was achieved for predicting the presence or absence of a shunt and 0.751 for venous PT. CONCLUSION: In patients with PT, clinical history and physical examination can achieve high performance at detecting a shunting lesion. Potentially treatable venous etiologies may also be suggested by relief with neck compression.
RESUMO
Dural arteriovenous fistulas with drainage into the spinal veins, classified as Cognard type 5, can be challenging to diagnose and treat. Brainstem and cervical spinal cord signal abnormalities on magnetic resonance imaging result from venous congestion, and can mimic tumor, infection, or inflammation.1-3 Transarterial and transvenous embolization techniques can be used to treat dural arteriovenous fistulas endovascularly. Efficacious transvenous treatment relies on the ability to safely catheterize the draining vein at the dural arteriovenous fistula site. Transvenous access options may seem limited in the setting of occluded venous sinuses. This case highlights the technical aspects of the transvenous approach to embolization of a transverse-sigmoid sinus dural arteriovenous fistula within an isolated sinus,4,5 demonstrating traversal of the occluded venous sinus from a contralateral approach.6,7[Media: see text].
RESUMO
Interest in transcranial MR imaging-guided focused ultrasound procedures has recently grown. These incisionless procedures enable precise focal ablation of brain tissue using real-time monitoring by MR thermometry. This article will provide an updated review on clinically applicable technical underpinnings and considerations of proton resonance frequency MR thermometry, the most common clinically used MR thermometry sequence.