Quantitative assessment of intracranial tumor response to dexamethasone using diffusion, perfusion and permeability magnetic resonance imaging

There is increasing interest in obtaining quantitative imaging parameters to aid in the assessment of tumor responses to treatment. In this study, the feasibility of performing integrated diffusion, perfusion and permeability magnetic resonance imaging (MRI) for characterizing responses to dexamethasone in intracranial tumors was assessed. Eight patients with glioblastoma, five with meningioma and three with metastatic carcinoma underwent MRI prior to and 48-72 h following dexamethasone administration. The MRI protocol enabled quantification of the volume transfer constant (K(trans)), extracellular space volume fraction (nu(e)), plasma volume fraction (nu(p)), regional cerebral blood flow (rCBF), regional cerebral blood volume (rCBV), longitudinal relaxation time (T(1)) and mean diffusivity (D(av)). All subjects successfully completed the imaging protocol for the presteroid and poststeroid scans. Significant reductions were observed after the treatment for K(trans), nu(e) and nu(p) in enhancing tumor as well as for T(1) and D(av) in the edematous brain in glioblastoma; on the other hand, for meningioma, significant differences were seen only in edematous brain T(1) and D(av). No significant difference was observed for any parameter in metastatic carcinoma, most likely due to the small sample size. In addition, no significant difference was observed for enhancing tumor rCBF and rCBV in any of the tumor types, although the general trend was for rCBV to be reduced and for rCBF to be more variable. The yielded parameters provide a wealth of physiologic information and contribute to the understanding of dexamethasone actions on different types of intracranial tumors.     

Dynamic contrast-enhanced MRI of vascular changes induced by the VEGF-signalling inhibitor ZD4190 in human tumour xenografts

Dynamic contrast-enhanced magnetic resonance imaging (DCEMRI) was used to examine the acute effects of treatment with an inhibitor of vascular endothelial growth factor (VEGF) signaling. ZD4190 is an orally bioavailable inhibitor of VEGF receptor-2 (KDR) tyrosine kinase activity, which elicits broad-spectrum antitumour activity in preclinical models following chronic once-daily dosing. Nude mice, bearing established (0.5-1.0 mL volume) human prostate (PC-3), lung (Calu-6) and breast (MDA-MB-231) tumor xenografts, were dosed with ZD4190 (p.o.) using a 1 day (0 and 22 h) or 7 day (0, 24, 48, 72, 96,120,144, and 166 h) treatment regimen. DCEMRI was employed 2 h after the last dose of ZD4190, using the contrast agent gadopentetate dimeglumine. Dynamic data were fit to a compartmental model to obtain voxelwise K(trans), the transfer constant for gadopentetate into the tumor. K(trans) was averaged over the entire tumor, and a multi-threshold histogram analysis was also employed to account for tumor heterogeneity. Reductions in K(trans) reflect reductions in flow, in endothelial surface area, and/or in vascular permeability. A vascular input function was obtained for each mouse simultaneously with the tumor DCEMRI data. ZD4190 treatment produced a dose-dependent (12.5-100 mg x kg(-1) per dose) reduction in K(trans) in PC-3 prostate tumors. At 100 mg x kg(-1), the largest concentration examined, ZD4190 reduced K(trans) in PC-3 tumors by 31% following 2 doses (1 day treatment regimen; p < 0.001) and by 53% following 8 doses (7 day regimen; p < 0.001). Comparative studies in the three models using a showed similar reductions in K(trans) for the lung and breast tumors using the histogram analysis, although the statistical significance was lost when K(trans) was averaged over the entire tumor. Collectively these studies suggest that DCEMRI using gadopentetate may have potential clinically, for monitoring inhibition of VEGF signaling in solid tumors.     

Prediction of gene therapy-induced tumor size changes by the vascularity changes measured using dynamic contrast-enhanced MRI

We studied the changes of tumor size after gene therapy treatment and its relationship with the changes of vascular volume as measured by dynamic contrast-enhanced magnetic resonance imaging (MRI), to investigate whether the vascular changes is predictive of tumor regression. The study was carried out using a spontaneously regressing rat tumor model (C6 Glioma grown subcutaneously in rats). Three rats were treated with recombinant adenoviruses expressing three genes, mouse interleukin 1-alpha (IL1-alpha), mouse interferon gamma (IFN-gamma), and human transforming growth factor beta (TGF-beta), one from each kind. Two rats were treated with saline as controls. Longitudinal studies were performed to monitor the changes of tumor volume (based on T(2)-weighted images) and the vascular volume (based on dynamic contrast enhanced images). In untreated animals, tumor regression was preceded by several days with a decrease in vascular volume. When the tumor growth was perturbed by expression of mouse IL-1alpha, the increase in vascular volume was correlated with the continuing growth in size, and the decrease in vascular volume was predictive of the onset of tumor regression. As new advances in immunotherapy in cancer treatment emerge, the ability to determine the efficacy of therapy as early as possible will enable optimization of treatment regiments. The vascularity changes measured by dynamic MRI may provide a means to serve for this purpose.     

MRI measurement of blood-brain barrier permeability following spontaneous reperfusion in the starch microsphere model of ischemia

Quantification of the acute increases in blood-brain barrier (BBB) permeability that occur subsequent to experimental ischemic injury has been limited to single time-point, invasive methodologies. Although permeability can be qualitatively assessed to visualise regional changes during sequential studies on the same animal using contrast-enhanced magnetic resonance imaging (MRI), quantitative information on the magnitude of change is required to compare barrier function during sequential studies on the same animal or between different animals. Recently, improvements in MRI tracer kinetic models and in MR hardware design mean that an estimate of permeability in vivo can now be obtained with acceptable accuracy and precision. We report here the use of such methods to study acute changes following spontaneous reperfusion in an animal model of ischemia. We have obtained estimates of BBB permeability following spontaneous reperfusion, subsequent to forebrain ischemia by unilateral carotid injection of starch microspheres in the rat. T2*-weighted and diffusion-trace imaging were used to monitor the initial reduction in CBF and the time-course of ischemia, respectively. Following reperfusion, an intraveneous bolus of dimeglumine gadopentetate (Gd-DTPA) and horseradish peroxidase (HRP) was given during a continuous acquisition of T1 maps with a 48 s temporal resolution. Permeability maps were constructed using a 4-compartment model; K(trans), the permeability-surface area product of the capillary walls was estimated to be 9.2 +/- 0.6 x 10(-4) min(-1) in the cortex. Visualisation of the regional extent of HRP extravasation on histological sections following termination of the experiment demonstrated very little correspondence to the region of Gd-DTPA leakage. Quantitative MRI assessment of BBB permeability following ischemia-reperfusion is consistent with published values obtained by invasive methods. Differences between Gd-DTPA-enhancement and HRP may reflect differences in the molecular size of the tracers.     

Integration of quantitative DCE-MRI and ADC mapping to monitor treatment response in human breast cancer: initial results

PURPOSE: The objective of this study was to assess changes in the water apparent diffusion coefficient (ADC) and in pharmacokinetic parameters obtained from the fast-exchange regime (FXR) modeling of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) during neoadjuvant chemotherapy in breast cancer. MATERIALS AND METHODS: Eleven patients with locally advanced breast cancer underwent MRI examination prior to and after chemotherapy but prior to surgery. A 1.5-T scanner was used to obtain T1, ADC and DCE-MRI data. DCE-MRI data were analyzed by the FXR model returning estimates of K(trans) (volume transfer constant), v(e) (extravascular extracellular volume fraction) and tau(i) (average intracellular water lifetime). Histogram and correlation analyses assessed parameter changes post-treatment. RESULTS: Significant (P < .05) changes or trends towards significance (P < .10) were seen in all parameters except tau(i), although there was qualitative reduction in tau(i) values post-treatment. In particular, there was reduction (P < .035) in voxels with K(trans) values in the range 0.2-0.5 min(-1) and a decrease (P < .05) in voxels with ADC values in the range 0.99 x 10(-3) to 1.35 x 10(-3) mm2/s. ADC and v(e) were negatively correlated (r = -.60, P < .02). Parameters sensitive to water distribution and geometry (T(1), v(e), tau(i) and ADC) correlated with a multivariable linear regression model. CONCLUSION: The analysis presented here is sensitive to longitudinal changes in breast tumor status; K(trans) and ADC are most sensitive to these changes. Relationships between parameters provide information on water distribution and geometry in the tumor environment.     

Reduced capillary perfusion and permeability in human tumour xenografts treated with the VEGF signalling inhibitor ZD4190: an in vivo assessment using dynamic MR imaging and macromolecular contrast media

We describe the use of perfusion-permeability magnetic resonance imaging (ppMRI) to study hemodynamic parameters in human prostate tumor xenografts, following treatment with the vascular endothelial growth factor-A (VEGF) receptor tyrosine kinase inhibitor, ZD4190. Using a macromolecular contrast agent (P792), a fast MR imaging protocol and a compartmental data analysis, we were able to demonstrate a significant simultaneous reduction in tumor vascular permeability, tumor vascular volume and tumor blood flow (43%, 30% and 42%, respectively) following ZD4190 treatment (100 mg/kg orally, 24 h and 2 h prior to imaging). This study indicates that MR imaging can be used to measure multiple hemodynamic parameters in tumors, and that tumor vascular permeability, volume and flow, can change in response to acute treatment with a VEGF signaling inhibitor.     

Detection of T2 changes in an early mouse brain tumor

The aim of the study was to determine the effect of early tumor growth on T₂ relaxation times in an experimental glioma model. A 9.4-T magnetic resonance imaging (MRI) system was used for the investigations. An animal model (n=12) of glioma was established using an intracranial inoculation of U87MGdEGFRvIII cells. The imaging studies were performed from Day 10 through Day 13 following tumor inoculation. Tumor blood vessel density was determined using quantitative immunochemistry. Tumor volume was measured daily using MR images. T₂ values of the tumor were measured in five areas across the tumor and calculated using a single exponential fitting of the echo train. The measurements on Days 10 and 13 after tumor inoculation showed a 20% increase in T₂. The changes in T₂ correlated with the size of the tumor. Statistically significant differences in T₂ values were observed between the edge of the tumor and the brain tissue on Days 11, 12 and 13 (P=.014, .008, .001, respectively), but not on Day 10 (P=.364). The results show that T₂-weighted MRI may not detect glioma during an early phase of growth. T₂ increases in growing glioma and varies heterogenously across the tumor.     

Temporal/spatial resolution improvement of in vivo DCE-MRI with compressed sensing-optimized FLASH

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) provides critical information regarding tumor perfusion and permeability by injecting a T(1) contrast agent, such as Gd-DTPA, and making a time-resolved measurement of signal increase. Both temporal and spatial resolutions are required to be high to achieve an accurate and reproducible estimation of tumor perfusion. However, the dynamic nature of the DCE experiment limits simultaneous improvement of temporal and spatial resolution by conventional methods. Compressed sensing (CS) has become an important tool for the acceleration of imaging times in MRI, which is achieved by enabling the reconstruction of subsampled data. Similarly, CS algorithms can be utilized to improve the temporal/spatial resolution of DCE-MRI, and several works describing retrospective simulations have demonstrated the feasibility of such improvements. In this study, the fast low angle shot sequence was modified to implement a Cartesian, CS-optimized, sub-Nyquist phase encoding acquisition/reconstruction with multiple two-dimensional slice selections and was tested on water phantoms and animal tumor models. The mean voxel-level concordance correlation coefficient for Ak(ep) values obtained from ×4 and ×8 accelerated and the fully sampled data was 0.87±0.11 and 0.83±0.11, respectively (n=6), with optimized CS parameters. In this case, the reduction of phase encoding steps made possible by CS reconstruction improved effectively the temporal/spatial resolution of DCE-MRI data using an in vivo animal tumor model (n=6) and may be useful for the investigation of accelerated acquisitions in preclinical and clinical DCE-MRI trials.     

Examining the acute effects of cediranib (RECENTIN, AZD2171) treatment in tumor models: a dynamic contrast-enhanced MRI study using gadopentate

Cediranib (RECENTIN, AZD2171) is a highly potent inhibitor of the tyrosine kinase activity associated with all three vascular endothelial growth factor (VEGF) receptors and is currently in Phase II/III clinical trials. Preclinically, cediranib inhibits VEGF signaling and angiogenesis in vivo and impedes solid tumor growth significantly. Clinically, changes observed using dynamic contrast-enhanced MRI (DCE-MRI) with gadopentate suggest that acute cediranib treatment compromises tumor hemodynamics. In this study, a DCE-MRI baseline scan using gadopentate was performed in nude rats bearing Lovo (human colorectal carcinoma) or C6 (rat glioma) tumors. Cediranib (3 mg/kg per day) or vehicle was then dosed orally (2, 26 and 50 h after the baseline scan; 12 rats per group) and a second scan acquired 2 h after the final dosing event. Mean values for K(trans) (Tofts and Kermode-derived) [Magn Reson Med 17 (1991) 357-67] and the initial area under the gadolinium concentration curve over the first 60 s (iAUC) were reduced significantly following cediranib treatment: K(trans) by 33% (P<.05) in both tumor models and iAUC by 23% (P>.05) and 33% (P>.005) in Lovo and C6, respectively. This is the first preclinical investigation to examine the effect of cediranib treatment on tumors by DCE-MRI with gadopentate.     

Assessment of early response to concurrent chemoradiotherapy in cervical cancer: value of diffusion-weighted and dynamic contrast-enhanced MR imaging

Purpose

To investigate diffusion-weighted (DWI) and dynamic contrast-enhanced MR imaging (DCE-MRI) as early response predictors in cervical cancer patients who received concurrent chemoradiotherapy (CCRT).

Materials and methods

Sixteen patients with cervical cancer underwent DWI and DCE-MRI before CCRT (preTx), at 1 week (postT1) and 4 weeks (postT2) after initiating treatment, and 1 month after the end of treatment (postT3). At each point, apparent diffusion coefficient (ADC) and DCE-MRI parameters were measured in tumors and gluteus muscles (GM). Tumor response was correlated with imaging parameters or changes in imaging parameters at each point.

Results

At each point, ADC, K^trans and V_e in tumors showed significant changes (P < 0.05), as compared with those of GM (P > 0.05). PostT1 tumor ADCs showed a significant correlation with tumor size response at postT2 (P = 0.041), and changes in tumor ADCs at postT1 had a significant correlation with tumor size (P = 0.04) and volume response (P = 0.003) at postT2. In tumors, preTx K^trans and V_e showed significant correlations with tumor size at postT3 (P = 0.011) and tumor size response at postT2 (P = 0.019), respectively.

Conclusion

DWI and DCE-MRI, as early biomarkers, have the potential to evaluate therapeutic responses to CCRT in cervical cancers.     

Blood oxygen level-dependent and perfusion magnetic resonance imaging: detecting differences in oxygen bioavailability and blood flow in transplanted kidneys

Functional magnetic resonance imaging (fMRI) is a powerful tool for examining kidney function, including organ blood flow and oxygen bioavailability. We have used contrast enhanced perfusion and blood oxygen level-dependent (BOLD) MRI to assess kidney transplants with normal function, acute tubular necrosis (ATN) and acute rejection. BOLD and MR-perfusion imaging were performed on 17 subjects with recently transplanted kidneys. There was a significant difference between medullary R2? values in the group with acute rejection (R2?=16.2/s) compared to allografts with ATN (R2?=19.8/s; P=.047) and normal-functioning allografts (R2?=24.3/s;P=.0003). There was a significant difference between medullary perfusion measurements in the group with acute rejection (124.4±41.1 ml/100 g per minute) compared to those in patients with ATN (246.9±123.5 ml/100 g per minute; P=.02) and normal-functioning allografts (220.8±95.8 ml/100 g per minute; P=.02). This study highlights the utility of combining perfusion and BOLD MRI to assess renal function. We have demonstrated a decrease in medullary R2? (decrease deoxyhemoglobin) on BOLD MRI and a decrease in medullary blood flow by MR perfusion imaging in those allografts with acute rejection, which indicates an increase in medullary oxygen bioavailability in allografts with rejection, despite a decrease in blood flow.     

Conventional MR imaging with simultaneous measurements of cerebral blood volume and vascular permeability in ganglioglioma

The conventional MR imaging appearance of gangliogliomas is often variable and nonspecific. Conventional MR images, relative cerebral blood volume (rCBV) and vascular permeability (K(trans)) measurements were reviewed in 20 patients with pathologically proven grade 1 and 2 gangliogliomas (n = 20) and compared to a group of grade 2 low-grade gliomas (n = 30). The conventional MRI findings demonstrated an average lesion size of 4.1 cm, contrast enhancement (n = 19), variable degree of edema, variable mass effect, necrosis/cystic areas (n = 8), well defined (n = 12), signal heterogeneity (n = 9), calcification (n = 4). The mean rCBV was 3.66 +/- 2.20 (mean +/- std) for grade 1 and 2 gangliogliomas. The mean rCBV in a comparative group of low-grade gliomas (n = 30), was 2.14 +/- 1.67. p Value < 0.05 compared with grade 1 and 2 ganglioglioma. The mean K(trans) was 0.0018 +/- 0.0035. The mean K(trans) in a comparative group of low-grade gliomas (n = 30), was 0.0005 +/- 0.001. p Value = 0.14 compared with grade 1 and 2 ganglioglioma. The rCBV measurements of grade 1 and 2 gangliogliomas are elevated compared with other low-grade gliomas. The K(trans), however, did not demonstrate a significant difference. Gangliogliomas demonstrate higher cerebral blood volume compared with other low-grade gliomas, but the degree of vascular permeability in gangliogliomas is similar to other low-grade gliomas. Higher cerebral blood volume measurements can help differentiate gangliogliomas from other low-grade gliomas.     

The effect of dexamethasone on tissue water distribution and proton relaxation in Panc02 tumors

The present experiments were conducted to determine the effects of dexamethasone mediated changes in tumor water distribution on proton relaxation times (T1, T2) in a murine pancreatic adenocarcinoma (Panc02). Spin lattice (T1) and spin-spin (T2) relaxation times were determined by ex vivo methods (10MHz) and by in vivo imaging techniques (6.25 MHz) at various intervals after single or multiple dexamethasone treatments. In complementary studies, dexamethasone mediated changes in tumor capillary permeability, tumor water distribution, relative tumor blood flow and tumor cell proliferation were also determined.

Proton spin lattice (T1) and spin-spin (T2 relaxation times for Panc02 tumors shortened within two hours of a single dexamethasone treatment. The time course and magnitude of this response was dexamethasone dose dependent. The time dependent changes in T1 and T2 after dexamethasone were similar at 10 MHz (ex vivo) and 6.25 MHz (in vivo imaging). Although dexamethasone produced little or no change in total tumor water content and tumor cell proliferation, transient changes in the physiologic distribution of tumor water were clearly demonstrated.

The data supports the idea that dexamethasone induced changes in the distribution of tumor water were mediated by changes in capillary permeability and tumor blood flow. These physiologic responses produced serial changes in tumor extracellular extravascular water content that were consistent with the observed changes in tumor T1 and T2. The results from these experiments might imply that therapy associated changes in tumor proton relaxation times may not only reflect changes in tissue water content, but may also reflect physiologic responses which alter the distribution of tissue water and solute.     

Sodium and proton diffusion MRI as biomarkers for early therapeutic response in subcutaneous tumors

The ability to quantitate early effects of tumor therapeutic response using noninvasive imaging would have a major impact in clinical oncology. One area of active research interest is the ability to use MR techniques to detect subtle changes in tumor cellular density. In this study, sodium and proton diffusion MRI were compared for their ability to detect early cellular changes in tumors treated with a cytotoxic chemotherapy. Subcutaneous 9L gliosarcomas were treated with a single dose of 1,3-bis(2-chloroethyl)-1-nitrosourea. Both sodium and diffusion imaging modalities were able to detect changes in tumor cellularity as early as 2 days after treatment, which continued to evolve as increased signal intensities reached a maximum approximately 8 days posttreatment. Early changes in tumor sodium and apparent diffusion coefficient values were predictive of subsequent tumor shrinkage, which occurred approximately 10 days later. Overall, therapeutical induced changes in sodium and diffusion values were found to have similar dynamic and spatial changes. These findings suggest that these imaging modalities detected similar early cellular changes after treatment. The results of this study support the continued clinical testing of diffusion MRI for evaluation of early tumor treatment response and demonstrate the complementary insights of sodium MRI for oncology applications.     

AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging

Dynamic contrast-enhanced MRI (DCE-MRI) was used to noninvasively evaluate the effects of AG-03736, a novel inhibitor of vascular endothelial growth factor (VEGF) receptor tyrosine kinases, on tumor microvasculature in a breast cancer model. First, a dose response study was undertaken to determine the responsiveness of the BT474 human breast cancer xenograft to AG-013736. Then, DCE-MRI was used to study the effects of a 7-day treatment regimen on tumor growth and microvasculature. Two DCE-MRI protocols were evaluated: (1) a high molecular weight (MW) contrast agent (albumin-(GdDTPA)(30)) with pharmacokinetic analysis of the contrast uptake curve and (2) a low MW contrast agent (GdDTPA) with a clinically utilized empirical parametric analysis of the contrast uptake curve, the signal enhancement ratio (SER). AG-013736 significantly inhibited growth of breast tumors in vivo at all doses studied (10-100 mg/kg) and disrupted tumor microvasculature as assessed by DCE-MRI. Tumor endothelial transfer constant (K(ps)) measured with albumin-(GdDTPA)(30) decreased from 0.034+/-0.005 to 0.003+/-0.001 ml min(-1) 100 ml(-1) tissue (P<.0022) posttreatment. No treatment-related change in tumor fractional plasma volume (fPV) was detected. Similarly, in the group of mice studied with GdDTPA DCE-MRI, AG-013736-induced decreases in tumor SER measures were observed. Additionally, our data suggest that 3D MRI-based volume measurements are more sensitive than caliper measurements for detecting small changes in tumor volume. Histological staining revealed decreases in tumor cellularity and microvessel density with treatment. These data demonstrate that both high and low MW DCE-MRI protocols can detect AG-013736-induced changes in tumor microvasculature. Furthermore, the correlative relationship between microvasculature changes and tumor growth inhibition supports DCE-MRI methods as a biomarker of VEGF receptor target inhibition with potential clinical utility.     

Magnetic resonance imaging measurements of vascular permeability and extracellular volume fraction of breast tumors by dynamic Gd-DTPA-enhanced relaxometry

Vascular permeability (k(ep), min(-1)) and extracellular volume fraction (v(e)) are tissue parameters of great interest to characterize malignant tumor lesions. Indeed, it is well known that tumors with high blood supply better respond to therapy than poorly vascularized tumors, and tumors with large extracellular volume tend to be more malignant than tumors showing lower extracellular volume. Furthermore, the transport of therapeutic agents depends on both extracellular volume fraction and vessel permeability. Thus, before treatment, these tissue parameters may prove useful to evaluate tumor aggressiveness and to predict responsiveness to therapy and variations during cytotoxic therapies could allow to assess treatment efficacy and early modified therapy schedules in case of poor responsiveness. As a consequence, there is a need to develop methods that could be routinely used to determine these tissue parameters. In this work, blood-tissue permeability and extracellular volume fraction information were derived from magnetic resonance imaging dynamic longitudinal relaxation rate (R(1)) mapping obtained after an intravenous bolus injection of Gd-DTPA in a group of 92 female patients with breast lesions, 68 of these being histologically proven to be with carcinoma. For the sake of comparison, 24 benign lesions were studied. The measurement protocol based on two-dimensional gradient echo sequences and a monoexponential plasma kinetic model was that validated in the occasion of previous animal experiments. As a consequence of neoangiogenesis, results showed a higher permeability in malignant than in benign lesions, whereas the extracellular volume fraction value did not allow any discrimination between benign and malignant lesions. The method, which can be easily implemented whatever the imaging system used, could advantageously be used to quantify lesion parameters (k(ep) and v(e)) in routine clinical imaging. Because of its large reproducibility, the method could be useful for intersite comparisons and follow-up studies.     

Functional magnetic resonance (fMR) imaging of a rat brain tumor model: implications for evaluation of tumor microvasculature and therapeutic response

Functional MR (fMR) imaging techniques based on blood oxygenation level dependent (BOLD) effects were developed and applied to a rat brain tumor model to evaluate the potential utility of the method for characterizing tumor growth and regression following treatment. Rats bearing 9L brain tumors in situ were imaged during inhalation of room air and after administration of 100% oxygen + acetazolamide (ACZ) injected 15 mg/kg intravenously. Pixel-to-pixel fMR maps of normalized signal intensity change from baseline values were calculated from T2 weighted spin echo (SE) images acquired pre- and post- oxygen + ACZ administration. Resultant fMR maps were then compared to gross histological sections obtained from corresponding anatomical regions. Regions containing viable tumor with increased cellular density and localized foci of necrotic tumor cells consistent with hypoxia were visualized in the fMR images as regions with decreased signal intensities, indicating diminished oxyhemoglobin concentration and blood flow as compared to normal brain. Histological regions having peritumor edema, caused by increased permeability of tumor vasculature, were visualized in the fMR images as areas with markedly increased signal intensities. These results suggest that fMR imaging techniques could be further developed for use as a non-invasive tool to assess changes in tumor oxygenation/hemodynamics, and to evaluate the pharmacologic effect of anti-neoplastic drugs.     

Enhanced MRI of tumors utilizing a new nitroxyl spin label contrast agent

Nitroxyl spin labels have been shown to be effective in vivo contrast agents for magnetic resonance imaging (MRI) of the central nervous system, myocardium, and urinary tract. A new pyrrolidine nitroxyl contrast agent (PCA) with better resistance to in vivo metabolic inactivation than previously tested agents was studied for its potential to enhance subcutaneous neoplasms in an animal model. Twenty-two contrast enhancement trials were performed on a total of 15 animals 4-6 weeks after implantation with human renal adenocarcinoma. Spin echo imaging was performed using a .35 T animal imager before and after intravenous administration of PCA in doses ranging from 0.5 to 3mM/kg. The intensity of tumor tissue in the images increased an average of 35% in animals receiving a dose of 3 mM/kg. The average enhancement with smaller doses was proportionately less. Tumor intensity reached a maximum within 15 min of injection. The average intensity difference between tumor and adjacent skeletal muscle more than doubled following administration of 3 mM/kg of PCA. Well-perfused tumor tissue was more intensely enhanced than adjacent poorly perfused and necrotic tissue.     

磁振灌流造影:对“流动敏感交互反转恢复”的评论(英文)

磁振造影在过去的数十年內取得了长足的进步,除了可提供生物解剖构造的资讯外,如今更可以进行组织灌流造影.磁振灌流造影主要可分成2种:动态磁感对比(Dynamic susceptibility Contrast)和动脉标记(Arterial Spin Labeling) .相较于动态磁感对比,动脉标记能非侵入性地观测灌流.动脉标记包括了数种技术:如CASL (continu-ous arterial spinlabeling) ,EPISTAR(echo planar imaging and signal targeting with al-ternating radiofrequency) ,PICORE(proxi mal inversion with a control for off-resonance effects)和FAIR(flow-sensitive alternating inversion recovery) .该文主要提供流动磁感交互反转恢复(FAIR)技术的综合介绍,包括其理论基础和实践,特别针对T1法在FAIR定量上的使用.定量上的困难亦将会在文章中被讨论.文章的最后总结FAIR之实际应用情形.     

Earlier detection of tumor treatment response using magnetic resonance diffusion imaging with oscillating gradients

An improved method for detecting early changes in tumors in response to treatment, based on a modification of diffusion-weighted magnetic resonance imaging, has been demonstrated in an animal model. Early detection of therapeutic response in tumors is important both clinically and in pre-clinical assessments of novel treatments. Noninvasive imaging methods that can detect and assess tumor response early in the course of treatment, and before frank changes in tumor morphology are evident, are of considerable interest as potential biomarkers of treatment efficacy. Diffusion-weighted magnetic resonance imaging is sensitive to changes in water diffusion rates in tissues that result from structural variations in the local cellular environment, but conventional methods mainly reflect changes in tissue cellularity and do not convey information specific to microstructural variations at sub-cellular scales. We implemented a modified imaging technique using oscillating gradients of the magnetic field for evaluating water diffusion rates over very short spatial scales that are more specific for detecting changes in intracellular structure that may precede changes in cellularity. Results from a study of orthotopic 9L gliomas in rat brains indicate that this method can detect changes as early as 24 h following treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea, when conventional approaches do not find significant effects. These studies suggest that diffusion imaging using oscillating gradients may be used to obtain an earlier indication of treatment efficacy than previous magnetic resonance imaging methods.