Biomedical subjects
Publications and source records attributed to C Rémy.
Perfusion MR Imaging is useful for initial diagnosis and follow up of brain tumors. Dynamic susceptibility contrast MR imaging is described. The limitations and advantages of this technique are discussed with respect to quantification and interpretation of results.
Vessel size index (VSI) measurements have been validated on rats bearing a glioma with high doses of contrast agent. The aim of this study was to evaluate the impact of using a reduced dose of contrast agent, necessary for clinical trials. Experiments were performed on rats at three doses of AMI-227 and clearly show higher VSI values at lower doses, whatever the region of interest (contralateral, peritumoral and intratumoral tissue). These results are in good correlation with Monte-Carlo simulations on healthy brain and suggest that only relative values can be obtained at clinical contrast agent doses and magnetic fields.
Two-dimensional J-resolved spectroscopy may be used to separate resonances which overlap in 1D NMR spectra. Coupled with spectroscopic imaging (SI), it would give unequivocal information on the distribution of such resonances. Multi-echo acquisition decreases the minimum experimental time of such 4D experiments. The water peak may be used for phase and chemical-shift reference. This study aimed to demonstrate the feasibility of J-resolved SI based on a multi-echo sequence and without water suppression, and its ability to separate the peaks for lactate and mobile lipid in a rat glioma. Experiments were performed on rat brain, without water suppression, at 7 T. The water signal was used for correcting the phase of the echoes. A FOCSY-like acquisition was used to collect the first part of the echoes at short echo times. Two different data processing methods were tested to overcome the problem of contaminations of metabolite signals by the intense water signal. Maps of N-acetylaspartate, choline, creatine, lactate and mobile lipids were obtained in vivo on a rat glioma in 70 min. The in-plane resolution was 2 mm2. The 2D spatially resolved, 2D J-resolved spectra enabled the separate mapping of lactate and mobile lipids.
While morphological and molecular events during angiogenesis in brain glioma have been extensively studied, the functional properties of tumour vessels have yet received little attention. We have determined changes in regional blood volume (BV) during graded hypoxic hypoxia using susceptibility contrast magnetic resonance imaging in a model of rat brain glioma. Nine anaesthetised and ventilated rats with C6 glioma were subjected to incremental reduction in the fraction of inspired oxygen (FiO(2)): 0.35, 0.25, 0.15, 0.12, 0.10 and reoxygenation to 0.35. At each episode, BV was determined in peritumoral, intratumoral and contralateral regions. Baseline BV values (FiO(2) of 0.35) were higher in peritumoral than in the contralateral and intratumoral regions. Progressive hypoxia resulted in a graded increase in BV in contralateral and peritumoral regions. At FiO(2) of 0.10, BV increases were comparable between these two regions: 49+/-22% (s.d.) and 28+/-17% with respect of control values, respectively. These BV changes reversed during the reoxygenation episode. By contrast, the intratumoral region had a significant increase in BV at FiO(2) of 0.10 only, with no evidence of return to the basal value during reoxygenation. Immunohistochemical staining of alpha-smooth muscle actin confirmed reactivity of vessels in the peritumoral region. Our findings indicate that peritumoral vessels present a vascular reactivity to hypoxia, which is comparable to that of nontumoral vessels. A method is thus available for noninvasively demonstrating whether any particular vascular modifying strategy results in the desired outcome in terms of tumour blood volume changes.
PURPOSE: To determine the perfusion-sensitive characteristics of cerebral dural metastases and compare them with the data on meningiomas. METHODS: Twenty-two patients presenting with dural tumor underwent conventional and dynamic susceptibility-contrast MR imaging: breast carcinoma metastases, two patients; colorectal carcinoma metastasis, one patient; lung carcinoma metastasis, one patient; Merkel carcinoma metastasis, one patient; lymphoma, one patient; meningiomas, 16 patients. The imaging characteristics were analyzed using conventional MR imaging. The cerebral blood volume (CBV) maps were obtained for each patient and the relative CBV (rCBV) in different areas was calculated using the ratio between the CBV in the pathological area (CBVp) and in the contralateral white matter (CBVn). RESULTS: The differentiation between a meningioma and a dural metastasis can be difficult using conventional MR imaging. The rCBVs of lung carcinoma metastasis (1 case: 1.26), lymphoma (1 case: 1.29), breast carcinoma metastasis (2 cases: 1.50,1.56) and rectal carcinoma metastasis (1 case: 3.34) were significantly lower than that of meningiomas (16 cases: mean rCBV = 8.97+/-4.34, range 4-18). Merkel carcinoma metastasis (1 case: 7.56) showed an elevated rCBV, not different from that of meningiomas. CONCLUSION: Dural metastases are sometimes indistinguishable from meningiomas using conventional MR imaging. rCBV mapping can provide additional information by demonstrating a low rCBV which may suggest the diagnosis of metastasis.
Vessel size imaging (VSI) for brain tumor characterization was evaluated and the vessel size index measured by MRI (VSIMRI) was correlated with VSI obtained by histology (VSIhisto). Blood volume (BV) and VSI maps were obtained on 12 rats by simultaneous measurements of R2* and R2, before and after the injection of a macromolecular contrast agent, AMI-227. Immunostaining of collagen IV in vessels was performed. An expression was derived for evaluating VSI from stereologic measurements on histology data (VSIhisto). On BV and VSI images obtained from large-size tumors (n = 9), three regions could be distinguished and correlated well with histological sections: a high BV region surrounding the tumor, a necrotic area where BV is very low, and a viable tumor tissue region showing lower BV but higher VSI than the normal rat cortex, with the presence of larger vessels. The quantitative analysis showed a good correlation (Spearman rank's rho = 0.74) between VSIhisto and VSIMRI with a linear regression coefficient of 1.17. The good correlation coefficient supports VSI imaging as a quantitative method for tumor vasculature characterization.
In C6 rat brain glioma, we have investigated the relation between hypoxia and the presence of lipid droplets in the cytoplasm of viable cells adjacent to necrosis. For this purpose, rats were stereotaxically implanted with C6 cells. Experiments were carried out by the end of the tumour development. A multifluorescence staining protocol combined with digital image analysis was used to quantitatively study the spatial distribution of hypoxic cells (pimonidazole), blood perfusion (Hoechst 33342), total vascular bed (collagen type IV) and lipid droplets (Red Oil) in single frozen sections. All tumours (n=6) showed necrosis, pimonidazole binding and lipid droplets. Pimonidazole binding occurred at a mean distance of 114 microm from perfused vessels mainly around necrosis. Lipid droplets were principally located in the necrotic tissue. Some smaller droplets were also observed in part of the pimonidazole-binding cells surrounding necrosis. Hence, lipid droplets appeared only in hypoxic cells adjacent to necrosis, at an approximate distance of 181 microm from perfused vessels. In conclusion, our results show that severe hypoxic cells accumulated small lipid droplets. However, a 100% colocalisation of hypoxia and lipid droplets does not exist. Thus, lipid droplets cannot be considered as a surrogate marker of hypoxia, but rather of severe, prenecrotic hypoxia.
We performed conventional and dynamic susceptibility-contrast MRI imaging in 38 patients with brain tumours: 20 with metastases (breast carcinoma: two; renal carcinoma: five; colorectal carcinoma: one; lung carcinoma: seven; melanoma: five), and 18 with high-grade astrocytomas. We obtained cerebral blood volume (CBV) maps and calculated the relative CBV (rCBV) in different areas using the ratio between the CBV in the pathological area (CBVp) and in the contralateral white matter (CBVn). We calculated the maximum rCBV (rCBVmax) for each tumour and compared the mean rCBVmax in each group of tumours. The mean rCBV of melanoma metastases (5.35+/-2.32, range 3.14-9.23) and of renal carcinoma metastases (8.17+/-2.39, range 5.41-11.64) were significantly greater than those of high-grade astrocytomas (2.61+/-1.17, range 1.3-5.0) ( P=0.002 and <0.001, respectively) and of lung carcinoma metastases (2.94+/-0.86, range 1.43-4.04) ( P=0.003 and 0.002). There was no statistically significant difference between the mean rCBV of lung metastases and of high-grade astrocytomas ( P=0.59). Large, solitary, necrotic metastases can be indistinguishable from high-grade astrocytomas using conventional MRI. Demonstration of an elevated rCBV which may suggest a hypervascular lesion such as renal carcinoma or melanoma.
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The value of extracellular pH (pH(e)) in tumors is an important factor in prognosisand choice of therapy. We demonstrate here that pH(e) can be mappedin vivo in a rat brain glioma by (1)H magnetic resonance spectroscopic imaging (SI) of the pH buffer (+/-)2-imidazole-1-yl-3-ethoxycarbonylpropionic acid (IEPA). (1)H SI also allowed us to map metabolites, and, to better understand the determinants of pH(e), we compared maps of pH(e), metabolites, and the distribution of the contrast agent gadolinium1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraaceticacid (Gd-DOTA). C6 cells injected in caudate nuclei of four Wistar rats gave rise to gliomas of approximately 10 mm in diameter. Three mmols of IEPA were injected in the right jugular vein from t = 0 to t = 60 min. From t = 50 min to t = 90 min, spin-echo (1)H SI was performed with an echo time of 40 ms in a 2.5-mm slice including the glioma (nominal voxel size, 2.2 microl). IEPA resonances were detected only within the glioma and were intense enough for pH(e) to be calculated from the chemical shift of the H2 resonance in almost all voxels of the glioma. (1)H spectroscopic images with an echo time of 136 ms were then acquired to map metabolites: lactate, choline-containing compounds (tCho), phosphocreatine/creatine, and N-acetylaspartate. Finally, T(1)-weighted imaging after injection of a bolus of Gd-DOTA gave a map indicative of extravasation. On average, the gradient of pH(e) (measured where sufficient IEPA was present) from the center to the periphery was not statistically significant. Mean pH(e) was calculated for each of the four gliomas, and the average was 7.084 +/- 0.017 (+/- SE; n = 4 rats), which is acid with respect to pH(e) of normal tissue. After normalization of spectra to their water peak, voxel-by-voxel comparisons of peak areas showed that N-acetylaspartate, a marker of neurons, correlated negatively with IEPA (P < 0.0001) and lactate (P < 0.05), as expected of a glioma surrounded by normal tissue. tCho (which may indicate proliferation) correlated positively with pH(e) (P < 0.0001). Lactate correlated positively with tCho (P < 0.0001), phosphocreatine/creatine (P < 0.001), and Gd-DOTA (P < 0.0001). Although lactate is exported from cells in association with protons, within the gliomas, no evidence was observed that pH(e) was significantly lower where lactate concentration was higher. These results suggest that lactate is produced mainly in viable, well-perfused, tumoral tissue from which proton equivalents are rapidly cleared.
High-grade brain tumors are known to have a high rate of glucose (Glc) consumption. Postmortem measurements have suggested that Glc content in experimental brain tumors is relatively low. We used magnetic resonance spectroscopy to investigate this, in vivo, in the brains of seven rats bearing intracerebral C6 gliomas. We combined the high spectral resolution allowed by two-dimensional proton nuclear magnetic resonance with spatial encoding by magnetic field gradient pulses to obtain in vivo maps of Glc, alanine, hypotaurine, aspartate, phosphoethanolamine, Glu/Gln, N-acetylaspartate (NAA), phosphocreatine/creatine (PCr/Cr), choline-containing compounds, and lactate (Lac) (some of which are involved in energy metabolism). Compared with normal brain tissue, the main differences found in the gliomas were that Glc, NAA, PCr/Cr, and aspartate concentrations were much lower, whereas concentrations of alanine, hypotaurine, phosphoethanolamine, and Lac were higher, whatever the extent of necrosis. A striking observation is the similarity of the NAA and Glc images: the concentrations of both metabolites are lower in the tumor than they are in the contralateral brain. If Glc was completely absent from the tumor tissue, and if the residual Glc level was due only to a partial volume effect like that for NAA, a neuronal marker, the ratio [Glc]tumor/[Glc]contralateral tissue, should be similar to that found for NAA. The ratio for Glc was 0.48 +/- 0.22 (+/- SD; n = 6), a ratio similar to that found for PCr/Cr (0.50 +/- 0.19) but significantly higher than that obtained for NAA (0.29 +/- 0.07). This observation indicates that a measurable Glc concentration is still present in the tumor tissue. Intense glycolysis in tumor cells may explain the increased production of Lac and alanine and decreased amount of Glc. These nuclear magnetic resonance measurements of metabolite concentrations are complementary to positron emission tomography, which measures Glc consumption.
Pulsed field gradient NMR was used to measure the root mean square displacement lambda of the NMR visible lipid molecules in C6 brain tumors in the rat at different diffusion times. For a distribution of spherical droplets of diameter with volume fraction xi(Phi(i)), the mean characteristic droplet diameter Phi(c) = square root of Sigma(i)xi(Phi(i)Phi(i)(2) was shown to be related to the root mean square displacement at long diffusion times by the simple relationship Phi(c)(2) = 10 lambda(2). In the range of diffusion times 100--530 msec, lambda was found to be independent of the diffusion time and equal to 1.35 +/- 0.22 microm and Phi(c) to 4.27 +/- 0.71 microm. The data reinforce the notion that the presence of lipid resonances in NMR spectra of tumors is due to lipid droplets. Light microscopy of histologic slices showed the presence of lipid droplets mainly in the necrotic region and in a layer of tumor cells surrounding the necrosis. Magn Reson Med 45:409-414, 2001.
T1-weighted magnetic resonance imaging (MRI) was used to evaluate the potential interest of a new Gd-based contrast agent, termed P760, to characterize brain tumor heterogeneity and vascularization and to delineate regions containing permeable vessels. The C6 rat glioma model was used as a model of high-grade glioblastoma. The signal enhancement was measured as a function of time in the vascular compartment and in different regions of interest (ROIs) within the tumor after the injection of 0.02 mmol x kg(-1) of P760. The results were compared to those obtained after the injection of 0.1 mmol x kg(-1) of Gd-DOTA. We showed that P760, in spite of a Gd concentration five times smaller, produces an enhancement in the blood pool similar to that produced by Gd-DOTA. It was shown that P760 makes possible an excellent delineation of regions containing vessels with a damaged blood-brain barrier (BBB). Images acquired 5-10 minutes after P760 injection showed the location of permeable vessels more accurately than Gd-DOTA-enhanced images. The enhancement produced in the tumor by P760 was, however, less than that produced by Gd-DOTA. The extravasation and/or diffusion rate of P760 in the interstitial medium were found to be strongly reduced, compared to those found with Gd-DOTA. This study suggests that the new contrast agent has promising capabilities in clinical imaging of brain tumors.
1H-MR spectroscopy in vivo is often hampered by poor spectral resolution. Spectral overlap can be avoided with two-dimensional spectroscopic techniques. Correlation peak imaging has been implemented to measure unambiguously the distribution of several metabolites in a rat brain glioma model. Acquisition-weighted spectroscopic imaging reduced the experimental time and provided excellent spatial localization. The choice of an appropriate spectral acquisition window granted good sensitivity. Spectroscopic images presenting a full two-dimensional spectrum in every image pixel were acquired in seven rats at 7 Tesla in 195 min, with a nominal voxel volume of 75 microl. Among other metabolites, the distribution of hypotaurine, phosphoethanolamine, alanine, and even glucose could be visualized both in the C6-glioma and in the unaffected brain.
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NMR imaging allow specific study of contrast variations due to intravascular agents. It is possible to measure regional cerebral blood volume (rCBV). In brain tumor, this parameter allow to characterize tumoral vascularisation and blood brain barrier lesions. We use today 1st pass bolus technic. Easy to perform in clinical practice, it is useful for differential diagnosis, prebiopsic planning and follow up of lesions. That should be particularly interesting to evaluate the anti-angiogenic treatment efficiency.
The aim of this work was to evaluate the potential of T(2)-weighted, steady-state susceptibility-enhanced contrast magnetic resonance imaging (MRI), to characterize brain tumor heterogeneity and tumor vascularization. In vivo T(2)-weighted MRI experiments were carried out on normal rats (n = 11) and rats bearing C6 glioma (n = 17), before and after the injection of a remanent superparamagnetic contrast agent. The DeltaR(2) variations of the transverse relaxation rate due to the injection of the contrast agent were used to generate relative cerebral blood volume (CBV) maps. Contrast enhancement of the tumor was shown to reflect tissue vascularization rather than leakage of the blood-brain barrier. The quantitative results clearly show the heterogeneity of tumor vascularization and reveal a high vessel density in the peripheral area (CBV(per) approximately 17.2 +/- 2.3 sec(-1)) and a low vessel density in the central area of the tumor (CBV(cen) approximately 2.5 +/- 0.5 sec(-1)). Magn Reson Med 42:754-761, 1999.
Contradictory experimental results and human trials have questioned the clinical relevance of the HSVtk/ganciclovir system. To bypass the problem of transfection efficiency, we used a glioma cell line stably expressing the HSVtk gene, which was also fully characterized from gene to protein. We also designed a more clinically relevant experimental protocol, consisting of late GCV delivery on large tumor formations. In short-term studies, histological examination revealed a significant decrease in tumor volume in GCV-treated animals from day 1 or from day 10 after cell inoculation. We observed that late GCV delivery is as efficient as early delivery, probably because GCV can reach tumor cells more easily when neoangiogenesis occurs. In long-term experiments, the survival of treated rats bearing 15-day tumors was improved by 60% compared with C6 control animals. Surprisingly, a 30% survival rate was observed in C6TK control animals. Nuclear magnetic resonance imaging demonstrated, in all surviving animals, a complete regression of tumors without mass effect. These results clearly demonstrate that the HSVtk/GCV system remains a potent therapeutic strategy, even when tested in large tumors, in contrast with the microscopic tumor formations previously reported.