A Preclinical Study to Explore Vasculature Differences Between Primary and Recurrent Tumors Using Ultrasound Doppler Imaging

The purpose of this preclinical study was to perform a longitudinal investigation of the function and morphology of the vasculatures of primary and recurrent tumors, because recurrent tumors have lower curability. Thus, elucidating differences in the features of the vasculatures of primary and recurrent tumors could help to improve tumor therapies. The transgenic adenocarcinoma of the mouse prostate tumors were transplanted in nonirradiated and with 25 Gy of preirradiation normal tissues to produce the primary and recurrent tumor models, respectively. The perfusion and branching index of tumor vasculatures were characterized to reveal the function and morphology information, respectively. The blood vessels were more dilated and continuous in recurrent tumors than in primary tumors. During tumor progression, the perfusion increased in primary tumors but did not change significantly in recurrent tumors. The tumor perfusion was lower in recurrent tumors than in primary tumors, whereas branching index in 2-D ultrasound images did not differ between the two tumor models. Furthermore, the introducing 3-D volumetric power Doppler image may have the potential for accurately revealing the morphologic features within tumors. The results of this study suggest that power Doppler imaging is an easily applied and rapid method for noninvasively assessing the vascular features of primary and recurrent tumors and for exploring differences between their vasculature pathways.     

Small Animal Imaging Center Design: The Facility at the UCLA Crump Institute for Molecular Imaging

Purpose

The growing number of mouse and rat experiments, coupled with advances in small-animal imaging systems such as microPET®, optical, microCAT?, microMR, ultrasound and microSPECT, has necessitated a common technical center for imaging small animals.

Procedures

At the UCLA Crump Institute for Molecular Imaging, we have designed and built a facility to support the research interests of a wide range of investigators from multiple disciplines. Requirements to satisfy both research and regulatory oversight have been critically examined. Support is provided for investigator training, study scheduling, data acquisition, archiving, image display, and analysis.

Results

The center has been in operation for more than 18 months, supporting more than 13,000 individual imaging procedures.

Conclusions

We have created a facility that maximizes our resource utilization while providing optimal investigator support, as well as the means to continually improve the quality and diversity of the science by integrating physical and biological sciences.

     

短暂性脑缺血发作的比较影像学初步研究

目的　评价CT平扫、CT脑灌注成像和经颅多普勒超声 (TCD)检查对短暂性脑缺血发作 (TIA)的诊断价值和限度。方法　对 2 0例临床诊断TIA的患者行头颅CT平扫、CT脑灌注成像和TCD检查 ,对其检查结果进行对比分析。结果　头颅CT平扫可排除其他脑内疾病 ,CT脑灌注成像显示颅内血流动力学异常改变 ,TCD则有助于明确TIA的病因。结论　 3种影像学方法结合应用 ,可获取更多的诊断信息 ,对TIA的诊断和治疗有重要意义。     

Non-invasive Small Vessel Imaging of Human Thyroid Using Motion-Corrected Spatiotemporal Clutter Filtering

Reliable assessment of small vessel blood flow in the thyroid, without using any contrast agents, can be challenging because of increased physiological motion resulting from its proximity to the pulsating carotid artery. In this study, we hypothesized that correction of tissue motion prior to singular value decomposition (SVD)-based clutter filtering can improve the coherency of the tissue components and, thus, may allow better clutter suppression and visualization of small vessels in the thyroid. We corroborated this hypothesis by conducting phantom and in vivo studies using a clinical ultrasound scanner implemented with compounded plane wave imaging. The phantom studies were conducted using a homogeneous tissue-mimicking phantom to study the impact of motion on the covariance of the spatiotemporal Doppler data, in the absence of blood activity. The non-invasive in vivo study was conducted on a 74-y-old woman with a thyroid nodule suspicious of malignancy. A rigid body-based motion correction was performed using tissue displacements obtained from 2-D normalized cross-correlation–based speckle tracking. Subsequently, the power Doppler images were computed using SVD-based spatiotemporal clutter filtering. The results from the phantom study revealed that motion can considerably reduce the covariance of the spatiotemporal data and, thus, increase the rank of the tissue components. When the phantom was subjected to a total translation displacement of 6 pixels over the entire ensemble, in each direction (axial and lateral), the covariance dropped by more than 25%. The results obtained from the non-invasive in vivo study indicated that visualization of small vessel blood flow improved with motion correction of the power Doppler ensemble. The contrast-to-noise ratio of the blood signal in motion-corrected power Doppler images was considerably higher (8.17 and 8.32 dB), compared with that obtained using the standard SVD approach at an optimal threshold (0.87 and 4.33 dB) and a lower singular value threshold (1.92 and 3.05 dB). Further, the covariance of the in vivo thyroid spatiotemporal data increased by approximately 10% with motion correction. These preliminary results indicate that motion correction can be used to improve the visualization of small vessel blood flow in the thyroid, without using any contrast agents. The results of this feasibility study were encouraging, and warrant further development and more in vivo validation in moving tissues and organs.     

Field Torso-Warming Modalities: A Comparative Study Using a Human Model

Objective. To compare four field-appropriate torso-warming modalities that do not require alternating-current (AC) electrical power, using a human model of nonshivering hypothermia. Methods. Five subjects, serving as their own controls, were cooled four times in 8°C water for 10–30 minutes. Shivering was inhibited by buspirone (30 mg) taken orally prior to cooling and intravenous (IV) meperidine (1.25 mg/kg) at the end of immersion. Subjects were hoisted out of the water, dried, and insulated and then underwent 120 minutes of one of the following: spontaneous warming only; a charcoal heater on the chest; two flexible hot-water bags (total 4 liters of water at 55°C, replenished every 20 minutes) applied to the chest and upper back; or two chemical heating pads applied to the chest and upper back. Supplemental meperidine (maximum cumulative dose of 3.5 mg/kg) was administered as required to inhibit shivering. Results. The postcooling afterdrop (i.e., the continued decrease in body core temperature during the early period of warming), compared with spontaneous warming (2.2°C), was less for the chemical heating pads (1.5°C) and the hot-water bags (1.6°C, p < 0.05) and was 1.8°C for the charcoal heater. Subsequent core rewarming rates for the hot-water bags (0.7°C/h) and the charcoal heater (0.6°C/h) tended to be higher than that for the chemical heating pads (0.2°C/h) and were significantly higher than that for spontaneous warming rate (0.1°C/h, p < 0.05). Conclusion. In subjects with shivering suppressed, greater sources of external heat were effective in attenuating core temperature afterdrop, whereas sustained sources of external heat effectively established core rewarming. Depending on the scenario and available resources, we recommend the use of charcoal heaters, chemical heating pads, or hot-water bags as effective means for treating cold patients in the field or during transport to definitive care.     

Cryo-image Analysis of Tumor Cell Migration, Invasion, and Dispersal in a Mouse Xenograft Model of Human Glioblastoma Multiforme

Purpose

The goals of this study were to create cryo-imaging methods to quantify characteristics (size, dispersal, and blood vessel density) of mouse orthotopic models of glioblastoma multiforme (GBM) and to enable studies of tumor biology, targeted imaging agents, and theranostic nanoparticles.

Procedures

Green fluorescent protein-labeled, human glioma LN-229 cells were implanted into mouse brain. At 20?C38?days, cryo-imaging gave whole brain, 4-GB, 3D microscopic images of bright field anatomy, including vasculature, and fluorescent tumor. Image analysis/visualization methods were developed.

Results

Vessel visualization and segmentation methods successfully enabled analyses. The main tumor mass volume, the number of dispersed clusters, the number of cells/cluster, and the percent dispersed volume all increase with age of the tumor. Histograms of dispersal distance give a mean and median of 63 and 56???m, respectively, averaged over all brains. Dispersal distance tends to increase with age of the tumors. Dispersal tends to occur along blood vessels. Blood vessel density did not appear to increase in and around the tumor with this cell line.

Conclusion

Cryo-imaging and software allow, for the first time, 3D, whole brain, microscopic characterization of a tumor from a particular cell line. LN-229 exhibits considerable dispersal along blood vessels, a characteristic of human tumors that limits treatment success.     

Preclinical Imaging of Therapy Response Using Metabolic and Apoptosis Molecular Imaging

Purpose  

Early after therapy, 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG) imaging is not always reliable due to the influx of inflammatory cells while apoptosis imaging offers a direct and early measurement of therapy effects. This study uses an improved apoptosis probe (^99mTc-hAnxA5) in combination with [¹⁸F]FDG imaging to evaluate therapy response.     

In Vivo Molecular Imaging Using Low-Boiling-Point Phase-Change Contrast Agents: A Proof of Concept Study

Sub-micron phase-change contrast agents (PCCAs) have been proposed as a tool for ultrasound molecular imaging based on their potential to extravasate and target extravascular markers and also because of the potential to image these contrast agents with a high contrast-to-tissue ratio. We compare in vivo ultrasound molecular imaging with targeted low-boiling-point PCCAs and targeted microbubble contrast agents. Both agents were targeted to the intravascular (endothelial) integrin α_vß₃via a cyclic RGD peptide (cyclo-Arg–Gly–Asp–D-Tyr–Cys) mechanism and imaged in vivo in a rodent fibrosarcoma model, which exhibits angiogenic microvasculature. Signal intensity was measured using two different techniques, conventional contrast-specific imaging (amplitude/phase modulation) and a droplet vaporization imaging sequence, which detects the unique signature of vaporizing PCCAs. Data indicate that PCCA-specific imaging is more sensitive to small numbers of bound agents than conventional contrast imaging. However, data also revealed that contrast from targeted microbubbles was greater than that provided by PCCAs. Both control and targeted PCCAs were observed to be retained in tissue post-vaporization, which was expected for targeted agents but not expected for control agents. The exact mechanism underlying this observation remains unknown.     

小肝癌的超声多普勒显像与病理分级相关性的研究

【目的】探讨小肝癌的超声多普勒血流显像特征与病理学分级的关系。【方法】应用彩色多普勒超声显像 (CDFI)和彩色多普勒能量图 (CDE) ,结合频谱多普勒波形分析 2 8例原发性小肝癌的血流显像 ,并探讨其与病理分级的相关性。【结果】CDFI和CDE的血流信号检出率在小肝癌高低分化两组中分别为 76 %和91% ;运用多普勒超声对结节内部的血流信号进行分级 ,结果表明低分化小肝癌组中CDE显像Ⅱ级和Ⅲ级血流明显多于CDFI。在低分化组中动脉输入性频谱和静脉输出性频谱的检出率显著高于高分化组 (P 分别小于 0 .0 5和 0 .0 1) ,而静脉输入性频谱的检出率显著低于高分化组 (P <0 .0 1)。【结论】CDE结合频谱多普勒波形分析可以对小肝癌的病理组织学分级进行预测 ,从而为临床制定治疗方案和预测疗效提供可靠的信息。     

复发与首发精神分裂症患者认知功能损害的比较研究

目的:分析首发与复发的精神分裂症患者认知功能损害的差别。方法:纳入首发精神分裂症患者23例(首发组),复发精神分裂症患者25例(复发组)及健康志愿者25例(对照),利用精神分裂症认知功能简明成套测评量表(BACS)评定3组认知功能,同时采用阳性和阴性症状量表(PANSS)对2组精神分裂症患者进行精神症状评估。结果:首发组与复发组精神症状评分的差异无统计学意义(P0.05),复发患者组的病程显著长于首发患者组(P=0.039);首发组与复发组BACS各项分测试结果均显著差于对照组(P0.05);复发组在语言流畅性及伦敦塔测试中的表现较首发患者组差(P=0.029,P=0.035),而语言记忆、数字序列、代币运动及符号编码等测试结果在2组间的差异无统计学意义(P0.05)。结论:认知功能损害在精神分裂症早期便已发生;且复发精神分裂症患者的在认知功能某些方面的损害较首发患者更为严重。     

Multimodality Imaging of Cancer Superoxide Anion Using the Small Molecule Coelenterazine

Purpose

We evaluated the small molecule coelenterazine as a potential reporter of cancer-associated superoxide anion in cell culture and in mice.

Procedures

The superoxide anion concentrations of various cancer cell lines were quantified by coelenterazine chemiluminescence in vitro. Coelenteramide fluorescence was detected via flow cytometry and fluorescent microscopy. Coelenterazine was used for the in vivo detection of cancer-associated superoxide anion using the 4T1 breast adenocarcinoma mouse model.

Results

Various cell lines in culture demonstrated different superoxide anion concentrations, with a signal range of 3.15?±?0.06 to 11.80?±?0.24 times that of background. In addition to chemiluminescent detection of coelenterazine, we demonstrated fluorescent detection of coelenteramide within the cytoplasm of cells. 4T1 murine mammary adenocarcinoma tumors in mice demonstrated significantly higher 2.13?±?0.19-fold coelenterazine-based chemiluminescence than that of surrounding normal tissues.

Conclusions

Collectively, our results indicate that coelenterazine can be used to assay superoxide anion concentrations in cultured cancer cells and in tumors growing in mice.

     

丙型肝炎病毒再感染与初次感染对比研究

用套武PCR法检测HCVRNA,对比研究了HCV再感染与初次感染.10例初次感染HCV者,9例为临床型肝炎,1例亚临床型,首次ALT升高距输血的时间为15～60天(平均37.9±13.9);抗-HCV和HCV-RNA阳性1年以上分别为10/10和7/10.5例再感染者,4例为临床型肝炎,1例亚临床型,ALT首次升高距输血时间为30～46天(平均34.8±6.4),抗-HCV和HCV RNA阳性1年以上分别为5/5和3/5.结果表明,HCV再感染与初次感染在临床表现、ALT异常、抗-HCV和HCV RNA阳性持续时间等均无明显差异,提示HCV感染后诱发的免疫力较差,再感染仍可发病.     

颞下颌关节磁共振成像与X线关节造影的对比性研究

目的　为口腔医学临床上颞下颌关节紊乱综合征 (TMJDS)的诊断提供更好的影像学参考。方法　在国产磁共振系统上 ,采用自行研制的颞下颌关节MRI表面线圈完成颞下颌关节区的MRI成像 ,并与关节造影进行了对比性研究。结果　MRI成像效果良好 ,更能清晰地显示出关节盘及其相关组织的结构状态 ,同时 ,由于对人体无任何放射性损害 ,无侵犯性操作 ,这些均是X线平片关节造影、CT无法比拟的。结论　采用本技术完成的颞下颌关节MRI成像 ,更有助于临床TMJDS的诊断。     

Modification of Aminosilanized Superparamagnetic Nanoparticles: Feasibility of Multimodal Detection Using 3T MRI, Small Animal PET, and Fluorescence Imaging

Purpose

The aim of our study was to modify an aminosilane-coated superparamagnetic nanoparticle for cell labeling and subsequent multimodal imaging using magnetic resonance imaging (MRI), positron emission tomography (PET), and fluorescent imaging in vivo.

Procedures

We covalently bound the transfection agent HIV-1 tat, the fluorescent dye fluorescein isothiocyanate, and the positron-emitting radionuclide gallium-68 to the particle and injected them intravenously into Wistar rats, followed by animal PET and MRI at 3.0 T. As a proof of principle hepatogenic HuH7 cells were labeled with the particles and observed for cell toxicity as well as detectability by MRI and biodistribution in vivo.

Results

PET imaging and MRI revealed increasing hepatic and splenic accumulation of the particles over 24 h. Adjacent in vitro studies in hepatogenic HuH7 cells showed a rapid intracellular accumulation of the particles with high labeling efficiency and without any signs of toxicity. In vivo dissemination of the labeled cells could be followed by dynamic biodistribution studies.

Conclusions

We conclude that our modified superparamagnetic nanoparticles are stable under in vitro and in vivo conditions and are therefore applicable for efficient cell labeling and subsequent multimodal molecular imaging. Moreover, their multiple free amino groups suggest the possibility for further modifications and might provide interesting opportunities for various research fields.     

Standardization and Optimization of Intraoperative Molecular Imaging for Identifying Primary Pulmonary Adenocarcinomas

Purpose

Intraoperative molecular imaging (IMI) is an emerging technology used to locate pulmonary adenocarcinomas and identify positive margins during surgery. Background noise and tissue autofluorescence have been major obstacles. The goal of this study is to optimize the image quality of folate receptor alpha (FRα) targeted IMI for pulmonary adenocarcinomas by modifying emission data.

Procedures

A total of 15 lung cancer patients were enrolled in a pilot study. In the first cohort, FRα upregulation within pulmonary adenocarcinoma tumors was confirmed by analyzing specimens from five pulmonary adenocarcinoma patients with flow cytometry and immunohistochemistry. Next, in a cohort of five additional patients, autofluorescence of intrathoracic structures and tissues was quantified. Lastly, five patients with tumors at various depths from the pleural surface were enrolled and received the FRα-targeted optical contrast agent, EC17. In this final cohort, resected pulmonary adenocarcinomas were imaged at a wide range of fluorescence exposure times (0 to 200 ms), various laser powers, and with unique filter configurations. Tumor-to-noise ratio (TNR) for images was generated using region of interest software.

Results

Pulmonary adenocarcinomas highly express FRα. Significant autofluorescence from native thoracic tissues was found with the highest fluorescent signals at the bronchial stump (547 ± 98, range 423–699), the pulmonary artery (267 ± 64, range 200–374), and cortical bone (266 ± 17, range 243–287). High levels of autofluorescence were appreciated after systemic administration of EC17; however, TNR was improved by altering exposure settings at the time of the imaging. Optimal fluorescent exposure time occurs at 40 ms (25 frames/s).

Conclusions

Exposure properties can be manipulated to maximize TNR thus allowing for successful intraoperative detection of pulmonary adenocarcinomas during surgery. Optimization of the conditions for intraoperative molecular imaging sets the stage for future clinical trials utilizing targeted IMI techniques which can aid the surgeon at the time of cancer resection.

     

MSCT冠状动脉成像与冠状动脉造影的对比研究

目的 :研究MSCT在冠状动脉成像中的临床应用价值。方法 :4 0例疑冠状动脉狭窄者行MSCT扫描 ,利用最大密度投影 (MIP)重建 ,2D重建 ,仿真内窥镜技术 ,了解冠状动脉病变情况 ,并与冠状动脉造影对比。结果 :4 0例 16 0支血管经MSCT成像 ,134支 (84 % )可用于影像学评价 ,2 6支 (16 % )不能评价。冠状动脉造影发现狭窄 4 6支 ,其中左前降支 (LAD)病变 18支 ,回旋支 (LCA)病变 12支 ,左主干 (LMA) 3支 ,右冠 (RCA)病变 13支。MSCT发现狭窄 4 1支 ,其中左前降支病变 14支 ,回旋支病变 12支 ,左主干病变 3支 ,右冠病变 12支。敏感性为 82 .6 % (38/ 4 6 ) ,特异性 97.3% (111/ 114 )。结论 :在控制心率的情况下 ,MSCT可作为冠状动脉狭窄的一种无创筛选检查方法。