RESUMO
BACKGROUND: Presence of intraplaque hemorrhage (IPH) is a known risk factor for stroke and plaque progression. Accurate and reproducible measurement of IPH volume are required for further risk stratification. PURPOSE: To develop a semiautomatic method to measure carotid IPH volume. STUDY TYPE: Retrospective. POPULATION: Patients scheduled for carotid endarterectomy and patients with 16-79% asymptomatic carotid stenosis by ultrasound. FIELD STRENGTH: 3T. SEQUENCE: Simultaneous noncontrast angiography and intraplaque hemorrhage (SNAP) MRI. ASSESSMENT: A semiautomated volumetric measurement of IPH using signal intensity thresholding of 3D SNAP volume was implemented. Fourteen carotid endarterectomy patients were enrolled to determine the signal intensity threshold of IPH using histology. Thirty-three patients with 16-79% asymptomatic stenosis were scanned twice within 1 month to evaluate reproducibility. The normalized SNAP intensity with the highest Youden index for predicting IPH on histology was used for thresholding. Scan-rescan reproducibility of IPH measurement was assessed using the intraclass correlation coefficient (ICC) and coefficient of variation (CV). STATISTICAL TESTS: Receiver operating characteristic curve, area under the curve, Cohen's kappa, intraclass correlation coefficient, coefficient of variance (CV), and paired t-test. RESULTS: IPH detection by the algorithm had substantial agreement with manual review (kappa: 0.92; 95% confidence interval [CI]: 0.83, 1.00) and moderate agreement with histology (kappa: 0.55; 95% CI: 0.34, 0.68). IPH volume measurements by the algorithm were strongly correlated with histology (Spearman's rho = 0.76, P = 0.002). IPH measurements were also reproducible, with ICCs of 0.86 (95% CI: 0.57, 0.96), 0.77 (95% CI: 0.32, 0.94), and 0.99 (95% CI: 0.93, 1.00) for maximum/mean normalized intensity and IPH volume, respectively. The corresponding CVs were 10.6%, 5.2%, and 11.8%. DATA CONCLUSION: IPH volume measurements on SNAP MRI are highly reproducible using semiautomatic measurement. Level of Evidence 2 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2019;50:1055-1062.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Hemorragia/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Placa Aterosclerótica/complicações , Placa Aterosclerótica/diagnóstico por imagem , Idoso , Artérias Carótidas/patologia , Feminino , Hemorragia/patologia , Humanos , Masculino , Placa Aterosclerótica/patologia , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
Background Ischemic stroke from carotid plaque embolism remains a major cause of morbidity in patients with type 2 diabetes mellitus (T2 DM ). However, the effect of early T2 DM and obesity on carotid remodeling and plaque burden remains elusive. We assessed carotid remodeling and plaque composition by carotid magnetic resonance imaging in patients with short-duration T2 DM compared with a sex- and age-matched control group. Methods and Results One hundred patients with T2 DM (duration <5 years) and 100 sex- and age-matched controls underwent bilateral carotid artery magnetic resonance imaging in a 1.5-T magnetic resonance imaging scanner. Plaque burden was quantified by normalized wall index, maximum wall thickness, maximum wall area, and minimum lumen size. Plaque morphology was quantified by calcified plaque volume, necrotic core volume, and loose matrix volume. Magnetic resonance imaging data were available for 149 and 177 carotid arteries from T2 DM patients and controls, respectively. Adjusted for age and sex, T2 DM was associated with increased plaque burden indicated by a higher normalized wall index (ratio 1.03 [95% confidence interval, 1.002; 1.06], P=0.03), and negative remodeling indicated by a lower minimum lumen area (ratio 0.81 [0.74; 0.89], P<0.001), and lower maximum wall area (ratio 0.94 [0.88; 1.00], P=0.048) compared with controls. In both T2 DM and controls, body mass index ≥30.0 kg/m2 was associated with an 80% increase in total calcified plaque volume, and a 44% increase in necrotic core volume compared with body mass index <25.0 kg/m2. Conclusions Short-duration T2 DM was associated with increased carotid plaque burden and negative remodeling. Obesity was associated with increased carotid artery necrotic core volume and calcification independently of diabetes mellitus status. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifier: NCT 00674271.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Estenose das Carótidas/diagnóstico por imagem , Diabetes Mellitus Tipo 2/epidemiologia , Obesidade/epidemiologia , Placa Aterosclerótica/diagnóstico por imagem , Remodelação Vascular , Idoso , Estenose das Carótidas/epidemiologia , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/epidemiologia , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/epidemiologiaRESUMO
Aberrant regulation of BCL-2 family members enables evasion of apoptosis and tumor resistance to chemotherapy. BCL-2 and functionally redundant counterpart, MCL-1, are frequently over-expressed in high-risk diffuse large B-cell lymphoma (DLBCL). While clinical inhibition of BCL-2 has been achieved with the BH3 mimetic venetoclax, anti-tumor efficacy is limited by compensatory induction of MCL-1. Voruciclib, an orally bioavailable clinical stage CDK-selective inhibitor, potently blocks CDK9, the transcriptional regulator of MCL-1. Here, we demonstrate that voruciclib represses MCL-1 protein expression in preclinical models of DLBCL. When combined with venetoclax in vivo, voruciclib leads to model-dependent tumor cell apoptosis and tumor growth inhibition. Strongest responses were observed in two models representing high-risk activated B-cell (ABC) DLBCL, while no response was observed in a third ABC model, and intermediate responses were observed in two models of germinal center B-cell like (GCB) DLBCL. Given the range of responses, we show that CIVO, a multiplexed tumor micro-dosing technology, represents a viable functional precision medicine approach for differentiating responders from non-responders to BCL-2/MCL-1 targeted therapy. These findings suggest that the combination of voruciclib and venetoclax holds promise as a novel, exclusively oral combination therapy for a subset of high-risk DLBCL patients.
Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzopiranos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Imino Furanoses/farmacologia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Animais , Antineoplásicos/uso terapêutico , Benzopiranos/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Humanos , Imino Furanoses/uso terapêutico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
The emergence of the concept of high-risk atherosclerotic plaque has led to considerable interest in noninvasive imaging techniques to identify high-risk features before clinical sequelae. For plaques in the carotid arteries, magnetic resonance imaging has undergone considerable histologic validation to link imaging features to indicators of plaque instability, including plaque burden, intraplaque hemorrhage, fibrous cap disruption, lipid rich necrotic core, and calcification. Recently introduced imaging technologies, especially those focused on three-dimensional imaging sequences, are now poised for integration into the clinical workup of patients with suspected carotid atherosclerosis. The purpose of this article is to review the carotid plaque magnetic resonance imaging techniques that are most ready for integration into the clinic.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Angiografia por Ressonância Magnética , Placa Aterosclerótica , Artérias Carótidas/química , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/complicações , Doenças das Artérias Carótidas/metabolismo , Doenças das Artérias Carótidas/patologia , Progressão da Doença , Fibrose , Hemorragia/diagnóstico por imagem , Hemorragia/patologia , Humanos , Lipídeos/análise , Necrose , Valor Preditivo dos Testes , Prognóstico , Medição de Risco , Fatores de Risco , Ruptura Espontânea , Índice de Gravidade de Doença , Calcificação Vascular/diagnóstico por imagem , Calcificação Vascular/patologiaRESUMO
The vision of a precision medicine-guided approach to novel cancer drug development is challenged by high intratumor heterogeneity and interpatient diversity. This complexity is rarely modeled accurately during preclinical drug development, hampering predictions of clinical drug efficacy. To address this issue, we developed Comparative In Vivo Oncology (CIVO) arrayed microinjection technology to test tumor responsiveness to simultaneous microdoses of multiple drugs directly in a patient's tumor. Here, in a study of 18 canine patients with soft tissue sarcoma (STS), CIVO captured complex, patient-specific tumor responses encompassing both cancer cells and multiple immune infiltrates following localized exposure to different chemotherapy agents. CIVO also classified patient-specific tumor resistance to the most effective agent, doxorubicin, and further enabled assessment of a preclinical autophagy inhibitor, PS-1001, to reverse doxorubicin resistance. In a CIVO-identified subset of doxorubicin-resistant tumors, PS-1001 resulted in enhanced antitumor activity, increased infiltration of macrophages, and skewed this infiltrate toward M1 polarization. The ability to evaluate and cross-compare multiple drugs and drug combinations simultaneously in living tumors and across a diverse immunocompetent patient population may provide a foundation from which to make informed drug development decisions. This method also represents a viable functional approach to complement current precision oncology strategies. Cancer Res; 77(11); 2869-80. ©2017 AACR.
Assuntos
Antineoplásicos/uso terapêutico , Imunomodulação/imunologia , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Animais , Linhagem Celular Tumoral , Cães , Resistência a Múltiplos Medicamentos , HumanosRESUMO
While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies.
Assuntos
Paclitaxel Ligado a Albumina/uso terapêutico , Compostos de Anilina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Sulfonamidas/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Paclitaxel Ligado a Albumina/administração & dosagem , Compostos de Anilina/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Apoptose/efeitos dos fármacos , Sinergismo Farmacológico , Camundongos , Neoplasias Pancreáticas/patologia , Sulfonamidas/administração & dosagemRESUMO
BACKGROUND: Intraplaque hemorrhage (IPH) is associated with atherosclerosis progression and subsequent cardiovascular events. We sought to develop a semi-automatic method with an optimized threshold for carotid IPH detection and quantification on MP-RAGE images using matched histology as the gold standard. METHODS: Fourteen patients scheduled for carotid endarterectomy underwent 3D MP-RAGE cardiovascular magnetic resonance (CMR) preoperatively. Presence and area of IPH were recorded using histology. Presence and area of IPH were also recorded on CMR based on intensity thresholding using three references for intensity normalization: the sternocleidomastoid muscle (SCM), the adjacent muscle and the automatically generated local median value. The optimized intensity thresholds were obtained by maximizing the Youden's index for IPH detection. Using leave-one-out cross validation, the sensitivity and specificity for IPH detection based on our proposed semi-automatic method and the agreement with histology on IPH area quantification were evaluated. RESULTS: The optimized intensity thresholds for IPH detection were 1.0 times the SCM intensity, 1.6 times the adjacent muscle intensity and 2.2 times the median intensity. Using the semi-automatic method with the optimized intensity threshold, the following IPH detection and quantification performance was obtained: sensitivities up to 59, 68 and 80 %; specificities up to 85, 74 and 79 %; Pearson's correlation coefficients (IPH area measurement) up to 0.76, 0.93 and 0.90, respectively, using SCM, the adjacent muscle and the local median value for intensity normalization, after heavily calcified and small IPH were excluded. CONCLUSIONS: A semi-automatic method with good performance on IPH detection and quantification can be obtained in MP-RAGE CMR, using an optimized intensity threshold comparing to the adjacent muscle. The automatically generated reference of local median value provides comparable performance and may be particularly useful for developing automatic classifiers. Use of the SCM intensity as reference is not recommended without coil sensitivity correction when surface coils are used.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Hemorragia/diagnóstico por imagem , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Placa Aterosclerótica , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Automação , Biópsia , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/patologia , Feminino , Hemorragia/patologia , Humanos , Interpretação de Imagem Assistida por Computador/normas , Imageamento por Ressonância Magnética/normas , Masculino , Pessoa de Meia-Idade , Variações Dependentes do Observador , Valor Preditivo dos Testes , Prognóstico , Curva ROC , Padrões de Referência , Reprodutibilidade dos TestesRESUMO
This brief data article summarizes the clinical risk factors and laboratory data of a group of subjects recruited for the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) and an associated magnetic resonance imaging (MRI) substudy. The sample is restricted to those on statin therapy at the time of enrollment and data are presented stratified by whether dynamic contrast enhanced MRI (DCE-MRI) markers of carotid plaque vascularity and inflammation were available or not. The data provided herein are directly related to the article "Longer Duration of Statin Therapy is Associated with Decreased Carotid Plaque Vascularity by Magnetic Resonance Imaging" [2].
RESUMO
OBJECTIVES: Simultaneous Non-contrast Angiography and intraPlaque hemorrhage (SNAP) technique was recently proposed for joint MRA and intraplaque hemorrhage (IPH) imaging. The purpose of this study is to validate SNAP's MRA performance in patients with suspected intracranial artery disease. METHODS: SNAP and time-of-flight (TOF) techniques with matched field of view and resolution were applied on 15 patients with suspected intracranial artery disease. Both techniques were evaluated based on their detection of luminal stenosis of bilateral middle cerebral arteries (MCA) and the delineation of smallest visible branches (SVB) of the MCA. Statistical analysis was conducted on the artery level. RESULTS: The SNAP MRA was found to provide similar stenosis detection performance when compared with TOF (Cohen's κ 0.79; 95% Confidence Interval: 0.56-0.99). For the SVB comparison, SNAP was found to provide significantly better small artery delineation than TOF (p = 0.017). Inter-reader reproducibility for both measurements on SNAP was over 0.7. SNAP also detected IPH lesions on 13% of the patients. CONCLUSIONS: The SNAP technique's MRA performance was optimized and compared against TOF for intracranial artery atherosclerosis imaging and was found to provide comparable stenosis detection accuracy. Along with its IPH detection capability, SNAP holds the potential to become a first-line screening tool for high risk intracranial atherosclerosis disease evaluation.
Assuntos
Hemorragia/patologia , Arteriosclerose Intracraniana/patologia , Angiografia por Ressonância Magnética/métodos , Adulto , Artérias/patologia , Estenose das Carótidas/patologia , Constrição Patológica , Meios de Contraste/química , Humanos , Masculino , Artéria Cerebral Média/fisiopatologia , Neuroimagem , Variações Dependentes do Observador , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
This study sought to discover which atherosclerotic plaque components co-localize with enhanced [(18)F]-fluorodeoxyglucose (FDG) uptake in carotid positron emission tomography (PET) images. Although in vivo PET currently lacks the resolution, high-resolution ex vivo FDG-microPET with histology validation of excised carotid plaque might accomplish this goal. Thirteen patients were injected with FDG before carotid endarterectomy. After excision, the plaque specimens were scanned by microPET and magnetic resonance imaging, and then serially sectioned for histological analysis. Two analyses were performed using generalized linear mixed models: (1) a PET-driven analysis which sampled high and low FDG uptake areas from PET images to identify their components in matched histology specimens; and (2) a histology-driven analysis where specific plaque components were selected and matched to corresponding PET images. In the PET-driven analysis, regions of high FDG uptake were more likely to contain inflammatory cells (p < 0.001) and neovasculature (p = 0.008) than regions of low FDG uptake. In the histology-driven analysis, regions with inflammatory cells (p = 0.001) and regions with loose extracellular matrix (p = 0.001) were associated with enhanced FDG uptake. Furthermore, areas of complex inflammatory cell infiltrate (co-localized macrophages, lymphocytes and foam cells) had the highest FDG uptake among inflammatory subgroups (p < 0.001). In conclusion, in carotid plaque, regions of inflammatory cell infiltrate, particularly complex one, co-localized with enhanced FDG uptake in high-resolution FDG-microPET images. Loose extracellular matrix and areas containing neovasculature also produced FDG signal. This study points to the potential ability of FDG-PET to detect the cellular components of the vulnerable plaque.
Assuntos
Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Fluordesoxiglucose F18/administração & dosagem , Placa Aterosclerótica , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Artérias Carótidas/patologia , Artérias Carótidas/cirurgia , Doenças das Artérias Carótidas/patologia , Doenças das Artérias Carótidas/cirurgia , Endarterectomia das Carótidas , Feminino , Fibrose , Humanos , Inflamação/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Neovascularização Patológica , Valor Preditivo dos Testes , Calcificação Vascular/diagnóstico por imagemRESUMO
Automatic in vivo segmentation of multicontrast (multisequence) carotid magnetic resonance for plaque composition has been proposed as a substitute for manual review to save time and reduce inter-reader variability in large-scale or multicenter studies. Using serial images from a prospective longitudinal study, we sought to compare a semi-automatic approach versus expert human reading in analyzing carotid atherosclerosis progression. Baseline and 6-month follow-up multicontrast carotid images from 59 asymptomatic subjects with 16-79 % carotid stenosis were reviewed by both trained radiologists with 2-4 years of specialized experience in carotid plaque characterization with MRI and a previously reported automatic atherosclerotic plaque segmentation algorithm, referred to as morphology-enhanced probabilistic plaque segmentation (MEPPS). Agreement on measurements from individual time points, as well as on compositional changes, was assessed using the intraclass correlation coefficient (ICC). There was good agreement between manual and MEPPS reviews on individual time points for calcification (CA) (area: ICC; 0.85-0.91; volume: ICC; 0.92-0.95) and lipid-rich necrotic core (LRNC) (area: ICC; 0.78-0.82; volume: ICC; 0.84-0.86). For compositional changes, agreement was good for CA volume change (ICC; 0.78) and moderate for LRNC volume change (ICC; 0.49). Factors associated with LRNC progression as detected by MEPPS review included intraplaque hemorrhage (positive association) and reduction in low-density lipoprotein cholesterol (negative association), which were consistent with previous findings from manual review. Automatic classifier for plaque composition produced results similar to expert manual review in a prospective serial MRI study of carotid atherosclerosis progression. Such automatic classification tools may be beneficial in large-scale multicenter studies by reducing image analysis time and avoiding bias between human reviewers.
Assuntos
Artérias Carótidas/patologia , Estenose das Carótidas/patologia , Meios de Contraste/administração & dosagem , Gadolínio DTPA/administração & dosagem , Interpretação de Imagem Assistida por Computador/métodos , Angiografia por Ressonância Magnética/métodos , Placa Aterosclerótica , Algoritmos , Automação , Progressão da Doença , Humanos , Estudos Longitudinais , Variações Dependentes do Observador , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
PURPOSE: To facilitate decision making in the oncology clinic, technologies have recently been developed to independently inject and assess multiple anticancer agents directly in a patient's tumor. To increase the flexibility of this approach beyond histological readouts of response, contrast-enhanced MRI was evaluated for the detection of cell death in living tumors after injection. METHODS: A six-needle arrayed microinjection device designed to provide head-to-head comparisons of chemotherapy responses in living tumors was used. Xenografted non-Hodgkin lymphoma tumors in athymic Nude-Foxn1(nu) mice were injected either with different doses of vincristine or with one needle each of vincristine, doxorubicin, bendamustine, prednisolone, mafosfamide, and a vehicle control. To assess drug responses, measurements of enhancement by T1-weighted contrast-enhanced MRI were made for individual sites at 24, 48, and 72 h after injection. For comparison, histological evaluations of cell death were obtained after tumor resection. RESULTS: Measurements of MRI enhancement at injection sites showed a significant (P < 0.001) positive regression slope as a function of vincristine dose. Average MRI measurements were closely correlated with cell death by hematoxylin and eosin staining (R = 0.81; P = 0.001). CONCLUSION: Contrast-enhanced MRI has the potential to replace or augment histological analyses of tumor responses to microinjected doses of chemotherapy agents with potential application in selecting optimal chemotherapy regimens. Magn Reson Med 76:946-952, 2016. © 2015 Wiley Periodicals, Inc.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Monitoramento de Medicamentos/métodos , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/tratamento farmacológico , Imageamento por Ressonância Magnética/métodos , Microinjeções/métodos , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Linfoma não Hodgkin/patologia , Camundongos , Camundongos Nus , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Resultado do TratamentoRESUMO
Hemodynamic wall shear stress (WSS) plays an important role in the initiation and progression of carotid atherosclerosis. This study aims at developing a technique to model WSS distribution based on point-wise geometric features that can be efficiently computed. Computational fluid dynamic analysis was performed for ten subjects. Surface curvatures, vascular radius, rate of change of radius along the longitudinal direction and standardized longitudinal/circumferential coordinates were computed on a point-wise basis for the arteries. Each of these point-wise geometric parameters was transformed to maximize the adjusted correlation coefficient. The transformed geometric parameters subsequently served as input variables of a multiple regression model. Multiple regression analysis revealed a significant relationship ([Formula: see text]) between WSS and three geometric parameters in internal and external carotid arteries (ICA and ECA). These three geometric parameters include vascular radius (ICA: [Formula: see text], ECA: [Formula: see text]), standardized longitudinal/circumference coordinates (ICA: [Formula: see text], ECA: [Formula: see text]) and Gaussian curvature (ICA: [Formula: see text], ECA: [Formula: see text]). The results suggest that the proposed geometric parameters can serve as risk indicator in large-scale clinical studies aiming at elucidating the roles of local geometric risk of atherosclerosis.
Assuntos
Aterosclerose/diagnóstico por imagem , Artérias Carótidas , Modelos Cardiovasculares , Artérias Carótidas/anatomia & histologia , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/fisiologia , Artéria Carótida Externa/anatomia & histologia , Artéria Carótida Externa/fisiologia , Artéria Carótida Interna/anatomia & histologia , Artéria Carótida Interna/fisiologia , Hemodinâmica , Humanos , Imageamento Tridimensional/métodos , Modelos Lineares , Imageamento por Ressonância Magnética , Dinâmica não Linear , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: Plaque neovasculature is a major route for lipoprotein and leukocyte ingress into plaques, and has been identified as a risk factor for carotid plaque disruption. Vp, a variable derived from pharmacokinetic modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), correlates with plaque neovasculature density. Because lipid-lowering therapy has been associated with regression of neovasculature in animal models, we sought to determine clinical correlates of carotid plaque neovasculature (as assessed by Vp) in participants on statin therapy for established cardiovascular disease. METHODS: 98 participants from an AIM-HIGH sub-study underwent DCE-MRI of their carotid arteries. Expert readers who were blinded to all clinical variables analyzed the MR images to measure carotid plaque Vp in all participants. Associations between Vp and duration of statin therapy and other clinical risk factors were analyzed. RESULTS: Prior duration of statin treatment at enrollment ranged from <1 year (21%) 1-5 years (40%) and >5 years (39%). In univariate analyses, shorter duration of statin therapy (P = 0.01), the presence of metabolic syndrome (P = 0.02), and higher body mass index (P = 0.01) and lipoprotein(a) (P = 0.01) were all significantly associated with higher baseline Vp values. In multivariate analyses, significant associations remained between shorter duration of statin therapy (P = 0.004) and lipoprotein(a) (P = 0.04). CONCLUSIONS: These are the first human, in vivo findings suggesting a relationship between duration of statin therapy and regression of carotid plaque neovasculature. Future longitudinal studies are warranted both to confirm this finding and to address whether changes in neovasculature may translate into change in risk for plaque disruption. CLINICALTRIALS. GOV IDENTIFIERS: NCT00880178, NCT01178320 and NCT00120289.
Assuntos
Artérias Carótidas/patologia , Doenças das Artérias Carótidas/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imageamento por Ressonância Magnética/métodos , Neovascularização Patológica/diagnóstico , Placa Aterosclerótica/tratamento farmacológico , Adulto , Doenças das Artérias Carótidas/patologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/patologia , Fatores de TempoRESUMO
PURPOSE: nab-paclitaxel demonstrates improved clinical efficacy compared with conventional Cremophor EL (CrEL)-paclitaxel in multiple tumor types. This study explored the distinctions in drug distribution between nab-paclitaxel and CrEL-paclitaxel and the underlying mechanisms. METHODS: Uptake and transcytosis of paclitaxel were analyzed by vascular permeability assay across human endothelial cell monolayers. The tissue penetration of paclitaxel within tumors was evaluated by local injections into tumor xenografts and quantitative image analysis. The distribution profile of paclitaxel in solid-tumor patients was assessed using pharmacokinetic modeling and simulation. RESULTS: Live imaging demonstrated that albumin and paclitaxel were present in punctae in endothelial cells and could be observed in very close proximity, suggesting cotransport. Uptake and transport of albumin, nab-paclitaxel and paclitaxel were inhibited by clinically relevant CrEL concentrations. Further, nab-paclitaxel causes greater mitotic arrest in wider area within xenografted tumors than CrEL- or dimethyl sulfoxide-paclitaxel following local microinjection, demonstrating enhanced paclitaxel penetration and uptake by albumin within tumors. Modeling of paclitaxel distribution in patients with solid tumors indicated that nab-paclitaxel is more dependent upon transporter-mediated pathways for drug distribution into tissues than CrEL-paclitaxel. The percent dose delivered to tissue via transporter-mediated pathways is predicted to be constant with nab-paclitaxel but decrease with increasing CrEL-paclitaxel dose. CONCLUSIONS: Compared with CrEL-paclitaxel, nab-paclitaxel demonstrated more efficient transport across endothelial cells, greater penetration and cytotoxic induction in xenograft tumors, and enhanced extravascular distribution in patients that are attributed to carrier-mediated transport. These observations are consistent with the distinct clinical efficacy and toxicity profile of nab-paclitaxel.
Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Sistemas de Liberação de Medicamentos , Endotélio Vascular/metabolismo , Nanopartículas/química , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Albumina Sérica/química , Animais , Antineoplásicos Fitogênicos/metabolismo , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/uso terapêutico , Transporte Biológico/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Carcinoma/tratamento farmacológico , Carcinoma/metabolismo , Carcinoma/patologia , Linhagem Celular Tumoral , Células Cultivadas , Endossomos/efeitos dos fármacos , Endossomos/metabolismo , Endossomos/patologia , Endotélio Vascular/citologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Infusões Intravenosas , Camundongos Nus , Microinjeções , Paclitaxel/metabolismo , Paclitaxel/farmacocinética , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Albumina Sérica/metabolismo , Albumina Sérica Humana , Distribuição Tecidual , Moduladores de Tubulina/administração & dosagem , Moduladores de Tubulina/metabolismo , Moduladores de Tubulina/farmacocinética , Moduladores de Tubulina/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto , Neoplasias PancreáticasRESUMO
A fundamental problem in cancer drug development is that antitumor efficacy in preclinical cancer models does not translate faithfully to patient outcomes. Much of early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent actual malignancies. To address this inconsistency, we have developed a technology platform called CIVO, which enables simultaneous assessment of up to eight drugs or drug combinations within a single solid tumor in vivo. The platform is currently designed for use in animal models of cancer and patients with superficial tumors but can be modified for investigation of deeper-seated malignancies. In xenograft lymphoma models, CIVO microinjection of well-characterized anticancer agents (vincristine, doxorubicin, mafosfamide, and prednisolone) induced spatially defined cellular changes around sites of drug exposure, specific to the known mechanisms of action of each drug. The observed localized responses predicted responses to systemically delivered drugs in animals. In pair-matched lymphoma models, CIVO correctly demonstrated tumor resistance to doxorubicin and vincristine and an unexpected enhanced sensitivity to mafosfamide in multidrug-resistant lymphomas compared with chemotherapy-naïve lymphomas. A CIVO-enabled in vivo screen of 97 approved oncology agents revealed a novel mTOR (mammalian target of rapamycin) pathway inhibitor that exhibits significantly increased tumor-killing activity in the drug-resistant setting compared with chemotherapy-naïve tumors. Finally, feasibility studies to assess the use of CIVO in human and canine patients demonstrated that microinjection of drugs is toxicity-sparing while inducing robust, easily tracked, drug-specific responses in autochthonous tumors, setting the stage for further application of this technology in clinical trials.
Assuntos
Antineoplásicos/química , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Linfoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Biomarcadores , Linhagem Celular Tumoral , Ciclofosfamida/análogos & derivados , Ciclofosfamida/química , Cães , Doxorrubicina/química , Sistemas de Liberação de Medicamentos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Camundongos , Camundongos Nus , Camundongos SCID , Transplante de Neoplasias , Prednisolona/química , Serina-Treonina Quinases TOR/metabolismo , Vincristina/químicaRESUMO
BACKGROUND: The aim of this study is to investigate the inter-scan reproducibility of kinetic parameters in atherosclerotic plaque using dynamic contrast-enhanced (DCE) cardiovascular magnetic resonance (CMR) in a multi-center setting at 3T. METHODS: Carotid arteries of 51 subjects from 15 sites were scanned twice within two weeks on 3T scanners using a previously described DCE-CMR protocol. Imaging data with protocol compliance and sufficient image quality were analyzed to generate kinetic parameters of vessel wall, expressed as transfer constant (K trans ) and plasma volume (v p ). The inter-scan reproducibility was evaluated using intra-class correlation coefficient (ICC) and coefficient of variation (CV). Power analysis was carried out to provide sample size estimations for future prospective study. RESULTS: Ten (19.6%) subjects were found to suffer from protocol violation, and another 6 (11.8%) had poor image quality (n=6) in at least one scan. In the 35 (68.6%) subjects with complete data, the ICCs of K trans and v p were 0.65 and 0.28, respectively. The CVs were 25% and 62%, respectively. The ICC and CV for v p improved to 0.73 and 28% in larger lesions with analyzed area larger than 25 mm2. Power analysis based on the measured CV showed that 50 subjects per arm are sufficient to detect a 20% difference in change of K trans over time between treatment arms with 80% power without consideration of the dropout rate. CONCLUSION: The result of this study indicates that quantitative measurement from DCE-CMR is feasible to detect changes with a relatively modest sample size in a prospective multi-center study despite the limitations. The relative high dropout rate suggested the critical needs for intensive operator training, optimized imaging protocol, and strict quality control in future studies.
Assuntos
Artérias Carótidas/patologia , Doenças das Artérias Carótidas/diagnóstico , Meios de Contraste , Gadolínio DTPA , Inflamação/diagnóstico , Angiografia por Ressonância Magnética/métodos , Placa Aterosclerótica , Idoso , Doenças das Artérias Carótidas/patologia , China , Estudos de Viabilidade , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Inflamação/patologia , Masculino , Pessoa de Meia-Idade , América do Norte , Pacientes Desistentes do Tratamento , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Fatores de TempoRESUMO
Stroke is among the leading causes of death and disability worldwide. Most strokes are ischemic, mostly caused by the blockage of a cerebral artery by a thrombotic embolus. Carotid atherosclerosis and the subsequent plaque rupture can be a major source of these emboli. It is well known that blood flow affects where atherosclerotic plaque will arise. In particular, vascular wall shear stress (WSS) has been linked to the initiation and progression of carotid plaque. However, it is difficult to measure WSS in vivo and it is time-consuming to compute WSS using computational fluid dynamics packages. The goals of this paper are (i) to identify a set of local geometric parameters that are correlated with WSS and (ii) to develop a regression model to predict WSS from the geometric parameters. We validated our regression model using the root mean squared error (RMSE), adjusted R(2) and Akaike information criterion (AIC). The experimental study involved six carotid arteries with the internal and external carotid arteries (ICA and ECA respectively) analyzed separately. The adjusted R(2)s for 9 of the 12 branches were higher than 0.8. Since the proposed local geometric parameters can be obtained efficiently, these parameters can potentially be used as carotid disease phenotypes that will allow for a much more cost-effective method to identify subjects with elevated stroke risk.
Assuntos
Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Hemorreologia/fisiologia , Algoritmos , Humanos , Placa Aterosclerótica/patologia , Placa Aterosclerótica/fisiopatologia , Análise de Regressão , Estresse MecânicoRESUMO
Local hemodynamic forces, such as wall shear stress (WSS), are thought to trigger cellular and molecular mechanisms that determine atherosclerotic plaque vulnerability to rupture. Magnetic resonance imaging has emerged as a powerful tool to characterize human carotid atherosclerotic plaque composition and morphology, and to identify plaque features shown to be key determinants of plaque vulnerability. Image-based computational fluid dynamics has allowed researchers to obtain time-resolved WSS information of atherosclerotic carotid arteries. A deeper understanding of the mechanisms of initiation and progression of atherosclerosis can be obtained through the comparison of WSS and plaque composition and morphology. To date, however, advance in knowledge has been limited greatly due to the lack of a reliable infrastructure to perform such analysis. The aim of this study is to establish a framework that will allow for the co-registration and analysis of the three-dimensional distribution of WSS and plaque components and morphology. The use of this framework will lead to future studies targeted to determining the role of WSS in atherosclerotic plaque progression and vulnerability.
Assuntos
Hemodinâmica , Imageamento Tridimensional , Placa Aterosclerótica/fisiopatologia , Artérias Carótidas/patologia , Artérias Carótidas/fisiopatologia , Humanos , Metabolismo dos Lipídeos , Imageamento por Ressonância Magnética , Necrose , Placa Aterosclerótica/diagnóstico , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Risco , Estresse MecânicoRESUMO
BACKGROUND AND PURPOSE: Autopsy studies have suggested a relationship between intraplaque hemorrhage (IPH) and vasa vasorum, which arise primarily from the adventitia. Adventitial vasa vasorum can be characterized in the carotid arteries by estimating perfusion parameters via dynamic contrast-enhanced MRI. The purpose of this investigation was to use dynamic contrast-enhanced MRI to test in vivo in a clinical population whether adventitial perfusion, indicative of vasa vasorum microstructure, is associated with IPH. METHODS: Symptomatic patients with carotid plaque ipsilateral to the ischemic event underwent bilateral carotid artery MRI examination, which included multicontrast sequences for detecting IPH and a dynamic contrast-enhanced MRI sequence for characterizing adventitial perfusion. Kinetic modeling of the dynamic contrast-enhanced MRI time series was performed to estimate adventitial vp (fractional plasma volume, reflecting local blood supply) and K(trans) (transfer constant, reflecting vessel surface area, and permeability). RESULTS: From the 27 patients (22 men; 69 ± 10 years of age) recruited, adventitial perfusion parameters were obtained in 50 arteries. The presence of IPH was associated with a significantly higher value in adventitial K(trans) (0.142 ± 0.042 vs 0.112 ± 0.029 min(-1); P<0.001) but not in vp (0.163 ± 0.064 vs 0.149 ± 0.062; P=0.338). This relationship remained after adjusting for symptomatic status, degree of stenosis, and other confounding factors. CONCLUSIONS: This study demonstrated an independent pathophysiological link between the adventitia and IPH and related it to the microstructure of adventitial vasa vasorum. Adventitial perfusion imaging may be useful in studying plaque pathogenesis, but further examination through prospective studies is needed.