Stefan Delorme

Pathophysiologic basis of contrast enhancement in breast tumors

While the diagnostic benefits of gadolinium (Gd)‐chelate contrast agents are firmly established in magnetic resonance imaging (MRI) of tumors, the pathophysiologic basis of the enhancement observed and its histopathologic correlate remained vague. Tumor angiogenesis is fundamental for growth and metastasis and also of interest in new therapeutic concepts. By correlative analysis of a) histology; b) vascular density (CD31); and c) vascular permeability (vascular permeability factor/vascular endothelial growth factor [VPF/VEGF]), we found a) significantly (P < 0.001) faster exchange rates in malignant compared with benign breast lesions; b) distinct differences in enhancement characteristics between the histologic types (invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ); and c) dependence of enhancement kinetics on the VPF/VEGF expression. The pathophysiologic basis for the differences in contrast enhancement patterns of tumors detectable by MRI is mainly due to vascular permeability, which leads to more characteristic differences than vascular density. MRI is able to subclassify malignant breast tumors due to their different angiogenetic properties. J. Magn. Reson. Imaging 1999;10:260–266.

Microcirculation and microvasculature in breast tumors: pharmacokinetic analysis of dynamic MR image series.

The purpose of this study was to quantify microcirculation and microvasculature in breast lesions by pharmacokinetic analysis of Gd‐DTPA‐enhanced MRI series. Strongly T1‐weighted MR images were acquired in 18 patients with breast lesions using a saturation‐recovery‐TurboFLASH sequence. Concentration‐time courses were determined for blood, pectoral muscle, and breast masses and subsequently analyzed by a two‐compartment model to estimate plasma flow and the capillary transfer coefficient per unit of plasma volume (F/VP, KPS/VP) as well as fractional volumes of the plasma and interstitial space (fP, fI). Tissue parameters determined for pectoral muscle (fP = 0.04 ± 0.01, fI = 0.09 ± 0.01, F/VP = 2.4 ± 1.3 min‐1, and KPS/VP = 1.2 ± 0.5 min‐1) and 10 histologically proven carcinomas (fP = 0.20 ± 0.07, fI = 0.34 ± 0.16, F/VP = 2.4 ± 0.7 min‐1, and KPS/VP = 0.86 ± 0.62 min‐1) agreed reasonable well with literature data. Best separation between malignant and benign lesions was obtained by the ratio KPS/F (0.35 ± 0.17 vs. 1.23 ± 0.65). The functional imaging technique presented appears promising to quantitatively characterize tumor pathophysiology. Its impact on diagnosis and therapy management of breast tumors, however, has to be evaluated in larger patient studies. Magn Reson Med 52:420–429, 2004.

Prognostic Significance of Focal Lesions in Whole-Body Magnetic Resonance Imaging in Patients With Asymptomatic Multiple Myeloma

PURPOSE With whole-body magnetic resonance imaging (wb-MRI), almost the whole bone marrow compartment can be examined in patients with monoclonal plasma cell disease. Focal lesions (FLs) detected by spinal MRI have been of prognostic significance in symptomatic multiple myeloma (sMM). In this study, we investigated the prognostic significance of FLs in wb-MRI in patients with asymptomatic multiple myeloma (aMM). PATIENTS AND METHODS Wb-MRI was performed in 149 patients with aMM. The prognostic significance of the presence and absence, as well as the number, of FLs for progression into sMM was analyzed. RESULTS FLs were present in 28% of patients. The presence per se of FLs and a number of greater than one FL were the strongest adverse prognostic factors for progression into sMM (P < .001) in multivariate analysis. A diffuse infiltration pattern in MRI, a monoclonal protein of 40 g/L or greater, and a plasma cell infiltration in bone marrow of 20% or greater were other adverse prognostic factors for progression-free survival in univariate analysis. CONCLUSION We recommend use of wb-MRI for risk stratification of patients with asymptomatic multiple myeloma.

Differentiation of Pancreas Carcinoma From Healthy Pancreatic Tissue Using Multiple b-Values: Comparison of Apparent Diffusion Coefficient and Intravoxel Incoherent Motion Derived Parameters

Objectives:To evaluate in detail the diagnostic performance of diffusion-weighted imaging (DWI) to differentiate pancreas carcinoma from healthy pancreas using the apparent diffusion coefficient (ADC) and parameters derived from the intravoxel incoherent motion (IVIM) theory. Materials and Methods:Twenty-three patients with pancreas carcinoma and 14 volunteers with healthy pancreas were examined at 1.5 Tesla using a single-shot echo-planar imaging DWI pulse sequence. Eleven b-values ranging from 0 to 800 s/mm2 were used. The acquisition was separated into blocks (b0, b25), (b0, b50),...(b0, b800) and each block was acquired in a single expirational breath-hold (TA = 26 seconds) to avoid motion artifacts. The ADC was calculated for all b-values using linear regression yielding ADCtot. By applying the IVIM model, which allows for the estimation of perfusion effects in DWI, the perfusion fraction f and the perfusion free diffusion parameter D were calculated. The diagnostic performance of ADC, f and D as a measure for the differentiation between healthy pancreas and pancreatic carcinoma was evaluated with receiver operating characteristics analysis. Results:In the healthy control group, the ADCtot ranged from 1.53 to 2.01 &mgr;m2/ms with a mean value of 1.71 ± 0.19 &mgr;m2/ms, the perfusion fraction f ranged from 18.5% to 40.4% with a mean value of 25.0 ± 6.2%, and the diffusion coefficient D from 0.94 to 1.28 &mgr;m2/ms with a mean value of 1.13 ± 0.15 &mgr;m2/ms. In patients with pancreas carcinoma, the ADCtot ranged from 0.98 to 1.81 &mgr;m2/ms with a mean value of 1.31 ± 0.24 &mgr;m2/ms, the perfusion fraction f ranged from 0% to 20.4% with a mean value of 8.59 ± 4.6% and the diffusion coefficient D from 0.74 to 1.60 &mgr;m2/ms with a mean value of 1.15 ± 0.22 &mgr;m2/ms. In comparison to healthy pancreatic tissue, a significant reduction of the perfusion fraction f and of ADCtot was found in pancreatic carcinoma (P < 0.00001, 0.0002, respectively). The f value showed more than a 10-fold higher significance level in distinguishing cancerous from normal tissue when compared with the ADCtot value. No significant difference in the diffusion coefficient D was observed between the 2 groups (P > 0.5). In the receiver operating characteristic-analyses, the area under curve for f was 0.991 and significantly larger than ADCtot (P < 0.05). f had the highest sensitivity, specificity, negative predictive value, and positive predictive value with 95.7%, 100%, 93.3%, and 100%, respectively. Conclusions:Using the IVIM-approach, the f value proved to be the best parameter for the differentiation between healthy pancreas and pancreatic cancer. The acquisition of several b-values strongly improved the stability of the parameter estimation thus increasing the sensitivity and specificity to 95.7% and 100% respectively. The proposed method may hold great promise for the non invasive, noncontrast-enhanced imaging of pancreas lesions and may eventually become a screening tool for pancreatic cancer.

Intravoxel incoherent motion MRI for the differentiation between mass forming chronic pancreatitis and pancreatic carcinoma.

Purpose:To determine which of the quantitative parameters obtained from intravoxel incoherent motion diffusion weighted imaging (DWI) is the most significant for the differentiation between pancreatic carcinoma and mass-forming chronic pancreatitis. Materials and Methods:Twenty-nine patients with pancreatic masses were included, 9 proved to have a mass-forming pancreatitis and 20 had a pancreatic carcinoma. The patients were studied using intravoxel incoherent motion DWI with 11 b-values and the apparent diffusion coefficient (ADC), the true diffusion constant (D) and the perfusion fraction (f) were calculated. The diagnostic strength of the parameters was evaluated using receiver operating characteristic analysis. Results:The ADC in chronic pancreatitis was higher than in pancreatic carcinoma with significant differences at b = 50, 75, 100, 150, 200, 300 s/mm2 (ADC50 = 3.17 ± 0.67 vs. 2.55 ± 1.09, ADC75 = 2.46 ± 0.4 vs. 1.93 ± 0.52, ADC100 = 2.28 ± 0.48 vs. 1.73 ± 0.45, ADC150 = 1.97 ± 0.26 vs. 1.63 ± 0.40, ADC200 = 1.98 ± 0.24 vs. 1.53 ± 0.28, and ADC300 = 1.76 ± 0.19 vs. 1.46 ± 0.31 × 10−3 mm2/s). No significant differences were found at b = 25, 400, 600, and 800 s/mm2 (ADC25 = 4.69 ± 0.65 vs. 4.04 ± 1.35, ADC400 = 1.57 ± 0.21 vs. 1.37 ± 0.30, ADC600 = 1.38 ± 0.18 vs. 1.24 ± 0.25, and ADC800 = 1.27 ± 0.10 vs. 1.18 ± 0.19 × 10−3 mm2/s) nor using ADCtot (1.42 ± 0.23 vs. 1.28 ± 0.12 × 10−3 mm2/s). The perfusion fraction f was significantly higher in pancreatitis compared with pancreatic carcinoma (16.3% ± 5.30% vs. 8.2% ± 4.00%, P = 0.0001). There was no significant difference between groups for D (1.07 ± 0.224 × 10−3 mm2/s for chronic pancreatitis and 1.09 ± 0.3 × 10−3 mm2/s for pancreatic carcinoma, P = 0.66). For f, the highest area under the curve (0.894) and combined sensitivity (80%) and specificity (89.9%) were found. Conclusions:There were significant differences in ADC50–300 between chronic pancreatitis and pancreatic carcinoma. Because D is not significantly different between groups, differences in ADC can be attributed mainly to differences in perfusion. The perfusion fraction f proved to be the superior DWI-derived parameter for differentiation of mass-forming pancreatitis and pancreatic carcinoma.

Accuracy of tumor size measurement in breast cancer using MRI is influenced by histological regression induced by neoadjuvant chemotherapy

Abstract. The aim of this study was to evaluate whether regressive changes after neoadjuvant chemotherapy for breast cancer affect the accuracy of preoperative MRI measurements of tumor size. Thirty-one patients with breast cancer underwent MRI before and after neoadjuvant treatment. Besides pre- and post-contrast T1-weighted MRI, dynamic MRI with high temporal resolution (turbo-FLASH) was performed. Contrast enhancement in dynamic MRI was quantified using a pharmacokinetic two-compartment model, where two parameters, amplitude and kep, were calculated and color coded on transversal parameter maps. Considering the conventional MR images, tumor diameters were measured on the color maps and compared with histological tumor size. Histological regression was scored on a five-point scale regarding cytopathic effects, reactive changes, and tumor cell reduction. The correlation between tumor sizes measured by MRI and histopathology was 0.83 (p<0.0007) in 12 tumors without regressive changes (score 0), and 0.48 (p<0.051) in 17 tumors with regressive changes scored 1 or 2, without any tendency for systematic over- or underestimation. In two cases without residual tumor (score 4), MRI likewise showed no signs of persistent tumor. The decrease of the contrast enhancement parameters was significantly more marked in tumors with signs of histological regression than in those without. Whenever MRI is used to judge the response of breast cancer to chemotherapy, the reader must be aware that therapy-induced changes may cause significant over- or underestimation of tumor size. We saw a high precision only when there was either no response – according to histological criteria – or when the tumor had regressed completely.

Evaluation of neoadjuvant chemotherapeutic response of breast cancer using dynamic MRI with high temporal resolution.

Abstract. The aim of this study was to evaluate changes in both size and contrast enhancement of breast tumors during neoadjuvant chemotherapy, using dynamic MRI with high temporal resolution. Patients with advanced breast cancer (n=21) underwent a 1.5-T MRI scan prior to and following neoadjuvant chemotherapy with four cycles. Dynamic contrast enhancement was measured using a fast turbo-FLASH sequence and quantified using a two-compartment model with the parameters kep and amplitude. Image analysis was done on images overlayed with a color map of parameters. The correlation between tumor diameter measured by histopathology and MRI was 0.7 (p<0.003). A reduction of tumor size after chemotherapy of more than 25% was associated with a decrease of both analyzed contrast enhancement parameters (kep: p<0.002; amplitude: p<0.006), where kep began to drop already after the first cycle of chemotherapy (p<0.008). A clear reduction of tumor size was only noted after the third cycle (p<0.008). In patients without tumor regression there was also a trend towards an early reduction of contrast enhancement.We assume that MRI with high temporal resolution and color mapping is a novel tool to assess therapeutic effects of neoadjuvant chemotherapy in breast tumors, which deserves further prospective evaluation.

Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma

OBJECTIVE Medullary thyroid carcinoma (MTC) is often associated with gain-of-function mutations in the RET proto-oncogene, which is found in all hereditary cases and most sporadic cases. The activated RET receptor tyrosine kinase can be inhibited by tyrosine kinase inhibitors in vitro. We evaluated the efficacy of treatment with imatinib mesylate, a tyrosine kinase inhibitor, in patients with advanced MTC. DESIGN AND PATIENTS In this open-label clinical trial, nine patients, eight with sporadic and one with hereditary MTC, with unresectable, measurable, progressive metastases were treated with imatinib mesylate 600 mg daily. The tumour response to imatinib was evaluated after 3, 6 and 12 months by computed tomography and after 1 month by (18)F-fluoro-2-deoxy D-glucose position-emission tomographic scanning. The median duration of therapy was 8 months. RESULTS Overall, stable disease occurred in five patients for up to 6 months and in one patient for up to 12 months, with a median duration of progression-free survival of 6 months. Four patients had progressive disease after 12 months. One patient stopped therapy after 2 weeks because of worsening of diarrhoea. Therapy was well tolerated, although transient mild-to-moderate nausea (n = 3), oedema (n = 3), diarrhoea (n = 2) and skin rash (n = 2) were observed. CONCLUSION Imatinib mesylate is well tolerated, no tumour remission was observed, only transient stable disease was achieved in some patients with advanced MTC.

Assessment of irradiated brain metastases by means of arterial spin-labeling and dynamic susceptibility-weighted contrast-enhanced perfusion MRI: Initial results

Rationale and Objectives:To assess if preradiation and early follow-up measurements of relative regional cerebral blood flow (rrCBF) can predict treatment outcome in patients with cerebral metastases and to evaluate rrCBF changes in tumor and normal tissue after stereotactic radiosurgery using arterial spin-labeling (ASL) and first-pass dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MRI. Methods:In 25 patients with a total of 28 brain metastases, DSC MRI and ASL perfusion MRI using the Q2TIPS sequence were performed with a 1.5-T unit. Measurements were performed prior to and at 6 weeks, 12 weeks, and 24 weeks after stereotactic radiosurgery. Follow-up examinations were completely available in 25 patients for Q2TIPS and 17 patients with 18 metastases for DSC MRI. The rrCBF of the metastases and the normal brain tissue was determined by a region-of-interest analysis. rrCBF values were correlated with the treatment outcome that was classified according to tumor volume changes at 6 months. Results:The alteration of the rrCBF at the 6-week follow-up was highly predictive for treatment outcome. A decrease of the rrCBF value predicted tumor response correctly in all metastases for Q2TIPS and in 13 of 16 metastases for DSC MRI. The pretherapeutic rrCBF was not able to predict treatment outcome. The rrCBF values in normal brain tissue affected by radiation doses less than 0.5 Gy remained unchanged after therapy. Conclusion:These preliminary results suggest that ASL and DSC MRI techniques determining rrCBF changes in brain metastases after stereotactic radiosurgery allow the prediction of treatment outcome.

Improved vascular opacification in cerebral computed tomography angiography with 80 kVp

Purpose:We sought to intraindividually compare computed tomography angiographies (CTAs) acquired at 80 kVp and 120 kVp with respect to vessel contrast, noise level, and radiation dose. Material and Methods:CTA was performed on a single-slice CT scanner using tube voltages of 80 kVp and 120 kVp in 29 patients with arteriovenous malformations. Mean Hounsfield Units (HU) were evaluated for different vessels and brain parenchyma. To determine contrast-to-noise ratios (CNRs), noise levels were estimated from phantom measurements. Results:The calculated effective dose to male/female patients was 0.4/0.5 mSv for 80 kVp and 0.7/0.8 mSv for 120 kVp. CT density in blood vessels was between 297 and 458 HU for 80 kVp and 152 and 229 HU for 120 kVp (P < 0.0001). Despite an increased noise level in the low-voltage images, the CNR was 26–59% higher at 80 kVp than at 120 kVp (P < 0.05). Conclusion:The use of a reduced tube potential leads to improved CNR in CTA of the cerebral vasculature and a markedly reduced radiation exposure to patients.