动态增强磁共振监测VEGF反义核酸对兔颌面部VX2肿瘤放疗的增敏作用

目的:研究动态增强磁共振成像(dynamic contrast enhanced magnetic resonance imaging,DCE-MRI)监测VEGF反义核酸对兔颌面部VX2肿瘤放疗后的影响。方法:24只颌面部VX2荷瘤兔模型随机分4组:放疗组(A组):给予16Gy放疗;VEGF反义核酸治疗组(B组):肿瘤局部注入VEGF反义核酸150μg;VEGF反义核酸联合放疗组(C组):16Gy放疗后立即局部肿瘤内注射VEGF反义核酸150μg;对照组(D组):肿瘤内注射300μl5%葡萄糖水溶液。治疗后第3天、14天分别行DCE-MRI检查,计算MER(Maximal enhancement ratio,最大强化率)及SLE(Slope of enhancement,强化率斜率)值,14天处死动物行病理检查和VEGF免疫组化染色。结果:C组治疗后14天肿瘤体积明显缩小,与治疗前和治疗后三天及其它组比较差别具有统计学意义(P<0.01)。MER值降低和SLE值降低,与治疗前比较差别有统计学意义(P<0.05)。病理切片显示肿瘤细胞水肿、出血,坏死,血管壁增厚闭塞,VEGF免疫阳性表达下降,经IHS评分与A...     

Modeling the Effect of Intra-Voxel Diffusion of Contrast Agent on the Quantitative Analysis of Dynamic Contrast Enhanced Magnetic Resonance Imaging

Quantitative dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) provides estimates of physiologically relevant parameters related to tissue blood flow, vascular permeability, and tissue volume fractions which can then be used for prognostic and diagnostic reasons. However, standard techniques for DCE-MRI analysis ignore intra-voxel diffusion, which may play an important role in contrast agent distribution and voxel signal intensity and, thus, will affect quantification of the aforementioned parameters. To investigate the effect of intra-voxel diffusion on quantitative DCE-MRI, we developed a finite element model of contrast enhancement at the voxel level. For diffusion in the range of that expected for gadolinium chelates in tissue (i.e., 1×10⁻⁴ to 4×10⁻⁴ mm²/s), parameterization errors range from −58% to 12% for K^trans, −9% to 8% for v_e, and −60% to 213% for v_p over the range of K^trans, v_e, v_p, and temporal resolutions investigated. Thus the results show that diffusion has a significant effect on parameterization using standard techniques.     

Dynamic Contrast Enhanced Magnetic Resonance Imaging of an Orthotopic Pancreatic Cancer Mouse Model

Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) has been limitedly used for orthotopic pancreatic tumor xenografts due to severe respiratory motion artifact in the abdominal area. Orthotopic tumor models offer advantages over subcutaneous ones, because those can reflect the primary tumor microenvironment affecting blood supply, neovascularization, and tumor cell invasion. We have recently established a protocol of DCE-MRI of orthotopic pancreatic tumor xenografts in mouse models by securing tumors with an orthogonally bent plastic board to prevent motion transfer from the chest region during imaging. The pressure by this board was localized on the abdominal area, and has not resulted in respiratory difficulty of the animals. This article demonstrates the detailed procedure of orthotopic pancreatic tumor modeling using small animals and DCE-MRI of the tumor xenografts. Quantification method of pharmacokinetic parameters in DCE-MRI is also introduced. The procedure described in this article will assist investigators to apply DCE-MRI for orthotopic gastrointestinal cancer mouse models.     

Arrival Time Correction for Dynamic Susceptibility Contrast MR Permeability Imaging in Stroke Patients

Purpose

To determine if applying an arrival time correction (ATC) to dynamic susceptibility contrast (DSC) based permeability imaging will improve its ability to identify contrast leakage in stroke patients for whom the shape of the measured curve may be very different due to hypoperfusion.

Materials and Methods

A technique described in brain tumor patients was adapted to incorporate a correction for delayed contrast delivery due to perfusion deficits. This technique was applied to the MRIs of 9 stroke patients known to have blood-brain barrier (BBB) disruption on T1 post contrast imaging. Regions of BBB damage were compared with normal tissue from the contralateral hemisphere. Receiver operating characteristic (ROC) analysis was performed to compare the detection of BBB damage before and after ATC.

Results

ATC improved the area under the curve (AUC) of the ROC from 0.53 to 0.70. The sensitivity improved from 0.51 to 0.67 and the specificity improved from 0.57 to 0.66. Visual inspection of the ROC curve revealed that the performance of the uncorrected analysis was worse than random guess at some thresholds.

Conclusions

The ability of DSC permeability imaging to identify contrast enhancing tissue in stroke patients improved considerably when an ATC was applied. Using DSC permeability imaging in stroke patients without an ATC may lead to false identification of BBB disruption.     

Monitoring Brain Tumor Vascular Heamodynamic following Anti-Angiogenic Therapy with Advanced Magnetic Resonance Imaging in Mice

Advanced MR imaging methods have an essential role in classification, grading, follow-up and therapeutic management in patients with brain tumors. With the introduction of new therapeutic options, the challenge for better tissue characterization and diagnosis increase, calling for new reliable non-invasive imaging methods. In the current study we evaluated the added value of a combined protocol of blood oxygen level dependent (BOLD) imaging during hyperoxic challenge (termed hemodynamic response imaging (HRI)) in an orthotopic mouse model for glioblastoma under anti-angiogenic treatment with B20-4.1.1, an anti-VEGF antibody. In glioblastoma tumors, the elevated HRI indicated progressive angiogenesis as further confirmed by histology. In the current glioblastoma model, B20-treatment caused delayed tumor progression with no significant changes in HRI yet with slightly reduced tumor vascularity as indicated by histology. Furthermore, fewer apoptotic cells and higher proliferation index were detected in the B20-treated tumors compared to control-treated tumors. In conclusion, HRI provides an easy, safe and contrast agent free method for the assessment of the brain hemodynamic function, an additionally important clinical information.     

MR Imaging Evaluation of Intracerebral Hemorrhages and T2 Hyperintense White Matter Lesions Appearing after Radiation Therapy in Adult Patients with Primary Brain Tumors

The purpose of our study was to determine the frequency and severity of intracerebral hemorrhages and T2 hyperintense white matter lesions (WMLs) following radiation therapy for brain tumors in adult patients. Of 648 adult brain tumor patients who received radiation therapy at our institute, magnetic resonance (MR) image data consisting of a gradient echo (GRE) and FLAIR T2-weighted image were available three and five years after radiation therapy in 81 patients. Intracerebral hemorrhage was defined as a hypointense dot lesion appearing on GRE images after radiation therapy. The number and size of the lesions were evaluated. The T2 hyperintense WMLs observed on the FLAIR sequences were graded according to the extent of the lesion. Intracerebral hemorrhage was detected in 21 (25.9%) and 35 (43.2) patients in the three- and five-year follow-up images, respectively. The number of intracerebral hemorrhages per patient tended to increase as the follow-up period increased, whereas the size of the intracerebral hemorrhages exhibited little variation over the course of follow-up. T2 hyperintense WMLs were observed in 27 (33.3%) and 32 (39.5) patients in the three and five year follow-up images, respectively. The age at the time of radiation therapy was significantly higher (p < 0.001) in the patients with T2 hyperintense WMLs than in those without lesions. Intracerebral hemorrhages are not uncommon in adult brain tumor patients undergoing radiation therapy. The incidence and number of intracerebral hemorrhages increased over the course of follow-up. T2 hyperintense WMLs were observed in more than one-third of the study population.     

In vivo Macrophage Imaging Using MR Targeted Contrast Agent for Longitudinal Evaluation of Septic Arthritis

Macrophages are key-cells in the initiation, the development and the regulation of the inflammatory response to bacterial infection. Macrophages are intensively and increasingly recruited in septic joints from the early phases of infection and the infiltration is supposed to regress once efficient removal of the pathogens is obtained. The ability to identify in vivo macrophage activity in an infected joint can therefore provide two main applications: early detection of acute synovitis and monitoring of therapy.In vivo noninvasive detection of macrophages can be performed with magnetic resonance imaging using iron nanoparticles such as ultrasmall superparamagnetic iron oxide (USPIO). After intravascular or intraarticular administration, USPIO are specifically phagocytized by activated macrophages, and, due to their magnetic properties, induce signal changes in tissues presenting macrophage infiltration. A quantitative evaluation of the infiltrate is feasible, as the area with signal loss (number of dark pixels) observed on gradient echo MR images after particles injection is correlated with the amount of iron within the tissue and therefore reflects the number of USPIO-loaded cells.We present here a protocol to perform macrophage imaging using USPIO-enhanced MR imaging in an animal model of septic arthritis, allowing an initial and longitudinal in vivo noninvasive evaluation of macrophages infiltration and an assessment of therapy action.     

超声造影联合声辐射力脉冲成像鉴别诊断盆腔肿物的价值

目的:评价超声造影及声辐射力脉冲成像技术在诊断及鉴别诊断盆腔良恶性肿块性质中的优越性。方法:分析术前超声造影及声辐射力脉冲成像技术在48例盆腔肿块中的检查结果,探讨两种技术对于肿块性质判定的应用价值。结果:48例中,良性肿块28例,恶性肿块20例。超声造影、声辐射力脉冲成像技术与常规超声相比,诊断的敏感性、特异性、漏诊率、误诊率、诊断准确性等指标均有统计学差异(P0.05),两者联合应用组与常规超声组相比上述指标的统计学差异更加明显(P0.01),超声造影技术和声辐射力脉冲成像技术在判断肿块良恶性方面诊断的敏感性、特异性、漏诊率、误诊率、诊断的准确性没有统计学差异(P0.05);超声造影与声辐射力脉冲成像对盆腔良恶性肿块定性诊断与病理诊断具有一致性,两者联合具有更好的一致性(Kappa=0.8362,0.7126,0.9241)。良恶性盆腔肿块中,实性为主者ARFI值均高于囊实混合性者;实性为主和囊实混合性的恶性盆腔肿块ARFI值均高于良性盆腔肿块,差异有统计学意义(均P0.05)。结论:实时超声造影联合声辐射力脉冲成像技术较常规超声更具优势,可提高盆腔肿物诊断及鉴别诊断的准确性。     

Evaluation of Potentially Predictive Markers for Anti-Angiogenic Therapy with Sunitinib in Recurrent Ovarian Cancer Patients

INTRODUCTION: In ovarian cancer, new therapeutic strategies are needed because the vast majority of patients develop a recurrence and resistance to platinum derivates. Attached to the AGO-OVAR2.11 study investigating the multityrosine kinase inhibitor sunitinib in recurrent platinum refractory ovarian cancers, this translational research project assesses the potential value of serum vascular endothelial growth factor (VEGF), soluble VEGF receptor-3 (sVEGFR-3), and angiopoietin-2 (Ang-2) levels for progression-free survival (PFS). MATERIALS AND METHODS: Longitudinal serum samples were taken while the patient was on study drugs. Serum concentration of VEGF, sVEGFR-3, and Ang-2 was determined by ELISA. The slope of the markers was correlated to the PFS. RESULTS: Patients showing a decrease in VEGF concentration had a median PFS of 10.5 months [confidence interval (CI), 2.89–12.25] compared to 2.9 months (CI, 1.48–5.32) in the case of an increase (P = .17). The stratified log-rank test showed a trend for longer PFS if a decrease of Ang-2 was observed (P = .089). Dichotomized in absolute decrease or increase, the PFS was 8.4 months (CI, 2.89–12.26) versus 2.7 months (CI, 1.05–5.32), respectively. Patients with a reduction of the sVEGFR-3 concentration had a median PFS of 4.76 months (CI 2.86–10.65) versus 8.61 months (CI, 1.05-not estimable) in patients with an increase of sVEGFR-3. This observation was statistically not significant in the log-rank test (P = .81). CONCLUSION: Ang-2 could potentially identify a patient population that might have a better PFS when under anti-angiogenic treatment, like the tyrosine kinase inhibitor sunitinib.     

Monitoring Early Response to Anti-Angiogenic Therapy: Diffusion-Weighted Magnetic Resonance Imaging and Volume Measurements in Colon Carcinoma Xenografts

Objectives

To evaluate the use of diffusion-weighted MRI (DW-MRI) and volume measurements for early monitoring of antiangiogenic therapy in an experimental tumor model.

Materials and Methods

23 athymic nude rats, bearing human colon carcinoma xenografts (HT-29) were examined before and after 6 days of treatment with regorafenib (n = 12) or placebo (n = 11) in a clinical 3-Tesla MRI. For DW-MRI, a single-shot EPI sequence with 9 b-values (10–800 s/mm²) was used. The apparent diffusion coefficient (ADC) was calculated voxelwise and its median value over a region of interest, covering the entire tumor, was defined as the tumor ADC. Tumor volume was determined using T2-weighted images. ADC and volume changes between first and second measurement were evaluated as classifiers by a receiver-operator-characteristic (ROC) analysis individually and combined using Fisher''s linear discriminant analysis (FLDA).

Results

All ADCs and volumes are stated as median±standard deviation. Tumor ADC increased significantly in the therapy group (0.76±0.09×10⁻³ mm²/s to 0.90±0.12×10⁻³ mm²/s; p<0.001), with significantly higher changes of tumor ADC than in the control group (0.10±0.11×10⁻³ mm²/s vs. 0.03±0.09×10⁻³ mm²/s; p = 0.027). Tumor volume increased significantly in both groups (therapy: 347.8±449.1 to 405.3±823.6 mm³; p = 0.034; control: 219.7±79.5 to 443.7±141.5 mm³; p<0.001), however, the therapy group showed significantly reduced tumor growth (33.30±47.30% vs. 96.43±31.66%; p<0.001). Area under the curve and accuracy of the ADC-based ROC analysis were 0.773 and 78.3%; and for the volume change 0.886 and 82.6%. The FLDA approach yielded an AUC of 0.985 and an accuracy of 95.7%.

Conclusions

Regorafenib therapy significantly increased tumor ADC after 6 days of treatment and also significantly reduced tumor growth. However, ROC analyses using each parameter individually revealed a lack of accuracy in discriminating between therapy and control group. The combination of both parameters using FLDA substantially improved diagnostic accuracy, thus highlighting the potential of multi-parameter MRI as an imaging biomarker for non-invasive early tumor therapy monitoring.     

An Optimized Triple Modality Reporter for Quantitative In Vivo Tumor Imaging and Therapy Evaluation

We present an optimized triple modality reporter construct combining a far-red fluorescent protein (E2-Crimson), enhanced firefly luciferase enzyme (Luc2), and truncated wild type herpes simplex virus I thymidine kinase (wttk) that allows for sensitive, long-term tracking of tumor growth in vivo by fluorescence, bioluminescence, and positron emission tomography. Two human cancer cell lines (MDA-MB-231 breast cancer and HT-1080 fibrosarcoma cancer) were successfully transduced to express this triple modality reporter. Fluorescence and bioluminescence imaging of the triple modality reporter were used to accurately quantify the therapeutic responses of MDA-MB-231 tumors to the chemotherapeutic agent monomethyl auristatin E in vivo in athymic nude mice. Positive correlation was observed between the fluorescence and bioluminescence signals, and these signals were also positively correlated with the ex vivo tumor weights. This is the first reported use of both fluorescence and bioluminescence signals from a multi-modality reporter construct to measure drug efficacy in vivo.     

纳米金在肿瘤成像和放射治疗领域的应用进展

纳米金颗粒以其优越的理化性质在医学领域发挥独特的作用.近年来越来越多的研究证实了纳米金在肿瘤早期诊断和治疗方面方面有重要作用,尤其是纳米金正被逐步应用肿瘤成像和治疗领域.本文从纳米金的性质,在肿瘤成像和放射治疗方面的应用进展等方面作一综述.     

Comprehensive Evaluation of the Anti-Angiogenic and Anti-Neoplastic Effects of Endostar on Liver Cancer through Optical Molecular Imaging

Molecular imaging enables non-invasive monitoring of tumor growth, progression, and drug treatment response, and it has become an important tool to promote biological studies in recent years. In this study, we comprehensively evaluated the in vivo anti-angiogenic and anti-neoplastic effects of Endostar on liver cancer based on the optical molecular imaging systems including micro-computer tomography (Micro-CT), bioluminescence molecular imaging (BLI) and fluorescence molecular tomography (FMT). Firefly luciferase (fLuc) and green fluorescent protein (GFP) dual labeled human hepatocellular carcinoma cells (HCC-LM3-fLuc-GFP cells) were used to establish the subcutaneous and orthotopic liver tumor model. After the tumor cells were implanted 14∼18 days, Endostar (5 mg/kg/day) was administered through an intravenous tail vein injection for continuous 14 days. The computer tomography angiography (CTA) and BLI were carried out for the subcutaneous tumor model. FMT was executed for the orthotopic tumor model. The CTA data showed that tumor vessel formation and the peritumoral vasculature of subcutaneous tumor in the Endostar treatment group was significantly inhibited compared to the control group. The BLI data exhibited the obvious tumor inhibition day 8 post-treatment. The FMT detected the tumor suppression effects of Endostar as early as day 4 post-treatment and measured the tumor location. The above data confirmed the effects of Endostar on anti-angiogenesis and tumor suppression on liver cancer. Our system combined CTA, BLI, and FMT to offer more comprehensive information about the effects of Endostar on the suppression of vessel and tumor formation. Optical molecular imaging system enabled the non-invasive and reliable assessment of anti-tumor drug efficacy on liver cancer.     

Gadolinium Enhanced 3D Proton Density Driven Equilibrium MR Imaging in the Evaluation of Cisternal Tumor and Associated Structures: Comparison with Balanced Fast-Field-Echo Sequence

Objectives

Although Gadolinium enhanced bFFE is commonly used to evaluate cisternal tumors, banding artifact may interrupt interpretation and adjacent nerve and vessels differentiation is known to be difficult. We analyzed the qualities of Gd enhanced 3D PDDE in the evaluation of cisternal tumors, comparing with bFFE.

Material and Methods

Forty five cisternal tumors (33 schwannoma and 12 meningioma) on both bFFE and PDDE were retrospectively reviewed. For quantitative analysis, contrast ratios of CSF to tumor and tumor to parenchyma (CR_C/T and CR_T/P) on both sequences were compared by paired t-test. For qualitative analysis, the readers gauged the qualities of the two MR sequences with respect to the degree of demarcating cisternal structures (tumor, basilar artery, AICA, trigeminal nerve, facial nerve and vestibulocochlear nerve).

Results

In quantitative analysis, CR_C/T and CR_T/P on 3D PDDE was significantly lower than that of 3D bFFE (p<0.01). In qualitative analysis, basilar artery, AICA, facial nerve and vestibulocochlear nerves were significantly better demarcated on 3D PDDE than on bFFE (p<0.01). The degree of demarcation of tumor on 3D PDDE was not significantly different with that on 3D bFFE (p = 0.13).

Conclusion

Although the contrast between tumor and the surrounding structures are reduced, Gd enhanced 3D PDDE provides better demarcation of cranial nerves and major vessels adjacent to cisternal tumors than Gd enhanced bFFE     

MR Molecular Imaging of Prostate Cancer with a Small Molecular CLT1 Peptide Targeted Contrast Agent

Tumor extracellular matrix has abundance of cancer related proteins that can be used as biomarkers for cancer molecular imaging. In this work, we demonstrated effective MR cancer molecular imaging with a small molecular peptide targeted Gd-DOTA monoamide complex as a targeted MRI contrast agent specific to clotted plasma proteins in tumor stroma. We performed the experiment of evaluating the effectiveness of the agent for non-invasive detection of prostate tumor with MRI in a mouse orthotopic PC-3 prostate cancer model. The targeted contrast agent was effective to produce significant tumor contrast enhancement at a low dose of 0.03 mmol Gd/kg. The peptide targeted MRI contrast agent is promising for MR molecular imaging of prostate tumor.     

Quantitative Liver MRI Combining Phase Contrast Imaging,Elastography, and DWI: Assessment of Reproducibility and Postprandial Effect at 3.0 T

Purpose

To quantify short-term reproducibility (in fasting conditions) and postprandial changes after a meal in portal vein (PV) flow parameters measured with phase contrast (PC) imaging, liver diffusion parameters measured with multiple b value diffusion-weighted imaging (DWI) and liver stiffness (LS) measured with MR elastography (MRE) in healthy volunteers and patients with liver disease at 3.0 T.

Materials and Methods

In this IRB–approved prospective study, 30 subjects (11 healthy volunteers and 19 liver disease patients; 23 males, 7 females; mean age 46.5 y) were enrolled. Imaging included 2D PC imaging, multiple b value DWI and MRE. Subjects were initially scanned twice in fasting state to assess short-term parameter reproducibility, and then scanned 20 min. after a liquid meal. PV flow/velocity, LS, liver true diffusion coefficient (D), pseudodiffusion coefficient (D*), perfusion fraction (PF) and apparent diffusion coefficient (ADC) were measured in fasting and postprandial conditions. Short-term reproducibility was assessed in fasting conditions by measuring coefficients of variation (CV) and Bland-Altman limits of agreement. Differences in MR metrics before and after caloric intake and between healthy volunteers and liver disease patients were assessed.

Results

PV flow parameters, D, ADC and LS showed good to excellent short-term reproducibility in fasting state (CV <16%), while PF and D* showed acceptable and poor reproducibility (CV = 20.4% and 51.6%, respectively). PV flow parameters and LS were significantly higher (p<0.04) in postprandial state while liver diffusion parameters showed no significant change (p>0.2). LS was significantly higher in liver disease patients compared to healthy volunteers both in fasting and postprandial conditions (p<0.001). Changes in LS were significantly correlated with changes in PV flow (Spearman rho = 0.48, p = 0.013).

Conclusions

Caloric intake had no/minimal/large impact on diffusion/stiffness/portal vein flow, respectively. PC MRI and MRE but not DWI should be performed in controlled fasting state.     

Quantitative Evaluation of Diffusion and Dynamic Contrast-Enhanced MR in Tumor Parenchyma and Peritumoral Area for Distinction of Brain Tumors

Purpose

To quantitatively evaluate the diagnostic efficiency of parameters from diffusion and dynamic contrast-enhanced MR which based on tumor parenchyma (TP) and peritumoral (PT) area in classification of brain tumors.

Methods

45 patients (male: 23, female: 22; mean age: 46 y) were prospectively recruited and they underwent conventional, DCE-MR and DWI examination. With each tumor, 10–15 regions of interest (ROIs) were manually placed on TP and PT area. ADC and permeability parameters (K^trans, Ve, Kep and iAUC) were calculated and their diagnostic efficiency was assessed.

Results

In TP, all permeability parameters and ADC value could significantly discriminate Low- from High grade gliomas (HGG) (p<0.001); among theses parameters, Ve demonstrated the highest diagnostic power (iAUC: 0.79, cut-off point: 0.15); the most sensitive and specific index for gliomas grading were K^trans (84%) and Kep (89%). While, in PT area, only K^trans could help in gliomas grading (P = 0.009, cut-off point: 0.03 min^-1). Moreover, in TP, mean Ve and iAUC of primary central nervous system lymphoma (PCNSL) and metastases were significantly higher than that in HGG (p<0.003). Further, in PT area, mean K^trans (p≤0.004) could discriminate PCNSL from HGG and ADC (p≤0.003) could differentiate metastases with HGG.

Conclusions

Quantitative ADC and permeability parameters from Diffusion and DCE-MR in TP and PT area, especially DCE-MR, can aid in gliomas grading and brain tumors discrimination. Their combined application is strongly recommended in the differential diagnosis of these tumor entities.     

Optimized Synthesis of PEG-Encapsulated Gold Nanorods for Improved Stability and Its Application in OCT Imaging with Enhanced Contrast

Gold nanorods (GNRs) are synthesized with a surfactant template, which often poses toxicity issues for biomedical applications. In addition, blue shift of longitudinal surface plasmon resonance (LSPR) peak of GNR is an inherent problem that needs to be addressed for time-course studies. In this work, we resolve these issues by optimizing the encapsulation of GNRs with polyethylene glycol (PEG) where biocompatibility is improved by ～20 % and blue shift over a period of 8 days is reduced from 20 nm in the case of CTAB-GNR to 2 nm for PEG-encapsulated GNR. The encapsulated GNRs were then bioconjugated for targeted dark-field imaging of cancer cells. As an application, we also demonstrate the contrast-enhancing capability of GNRs in optical coherence tomography (OCT) imaging of tumor xenograft where the LSPR closely matches the OCT excitation wavelength. Our study proves that incorporating GNRs enhances the contrast of tumor tissue interfaces along with a considerable broadening in OCT depth profile by six times.