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Background: Fertility preservation is an important concern in breast cancer patients. In the present investigation, we set out to create a specific protocol of controlled ovarian stimulation (cos) for oocyte cryopreservation in breast cancer patients. Methods: From November 2014 to December 2016, 109 patients were studied. The patients were assigned to a specific random-start ovarian stimulation protocol for oocyte cryopreservation. The endpoints were the numbers of oocytes retrieved and of mature oocytes cryopreserved, the total number of days of ovarian stimulation, the total dose of gonadotropin administered, and the estradiol level on the day of the trigger. Results: Mean age in this cohort was 31.27 ± 4.23 years. The average duration of cos was 10.0 ± 1.39 days. The mean number of oocytes collected was 11.62 ± 7.96 and the mean number of vitrified oocytes was 9.60 ± 6.87. The mean estradiol concentration on triggering day was 706.30 ± 450.48 pg/mL, and the mean dose of gonadotropins administered was 2610.00 ± 716.51 IU. When comparing outcomes by phase of the cycle in which cos was commenced, we observed no significant differences in the numbers of oocytes collected and vitrified, the length of ovarian stimulation, and the estradiol level on trigger day. The total dose of follicle-stimulating hormone and human menopausal gonadotropin administered was statistically greater in the group starting cos in the luteal phase than in the group starting in the late follicular phase. Conclusions: Our results suggest that using a specific protocol with random-start ovarian stimulation for oocyte cryopreservation in breast cancer patients is effective and could be offered to young women undergoing oncologic treatment.

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The use of functional magnetic resonance imaging (fMRI) techniques for evaluation of pharmacologic stimuli has great potential for understanding neurotransmitter dynamics for a number of brain disorders, such as drug abuse, schizophrenia, epilepsy, or neurodegeneration. Unfortunately, blood oxygenation level-dependent (BOLD) imaging at common fields strengths, such as 1.5 or 3 T, has very low sensitivity and contrast-to-noise ratios (CNRs). We demonstrate here the utility of using an intravascular superparamagnetic iron oxide contrast agent with a long plasma half-life for evaluation of hemodynamic changes related to dopaminergic stimuli using amphetamine or the cocaine analog 2beta-carbomethoxy-3beta-(4-fluorophenyl)tropane (CFT). We refer to this technique as increased relaxation with iron oxide nanoparticles (IRON). Results obtained here show that even at field strengths as high as 4.7 T, one can obtain increases in CNR by factors of 2-3 over BOLD imaging that lead to greater than an order of magnitude increase in statistical power with greatly increased sensitivity to hemodynamic changes in brain regions difficult to observe using BOLD imaging. Furthermore, use of the intravascular contrast agent allows for a meaningful physiologic parameter to be measured (relative cerebral blood volume (rCBV)), compared to conventional BOLD imaging.

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Contrast-enhanced coronary angiography has become an important technique for magnetic resonance (MR) coronary artery imaging. However, the relationship between the quality of the coronary artery images and blood T1 has not yet been fully explored. In this paper, we assessed this relationship in an animal model by using a prototypical blood pool agent. With accumulated injections of this agent, the blood T1 would be maintained at different levels. The measured blood T1 values in vivo were 147 +/- 3, 82 +/- 6, 48 +/- 4, 40 +/- 3, and 30 +/- 8 msec (N = 7). Fixed and variable flip angle schemes were used in coronary artery imaging. The signal to noise ratios (SNR) of coronary arteries were measured and the image quality was assessed. It was found that blood T1 less than 80 msec might be desired. No statistically significant difference was observed between two flip angle schemes. There was better vessel definition using variable flip angle at blood T1 lower than 50 msec. Understanding this relationship may be beneficial to optimizing image protocol and/or design of blood pool contrast agents for contrast-enhanced coronary angiography.

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Initial evaluation of a new blood pool agent, B-22956/1, for pulmonary imaging was performed in five domestic pigs with artificial embolism. Pre-embolism 3D pulmonary perfusion images were first acquired by injecting an extravascular agent, gadoteridol. The pulmonary arteries of the pigs were then occluded by the artificial emboli. Post-embolism perfusion scans were subsequently performed by injecting B-22956/1. Additional post-embolism high-spatial-resolution angiograms were also acquired. Parenchyma perfusion deficits were well depicted in the post-embolism perfusion maps. The post-embolism angiography clearly revealed the location and extent of the filling defects in the pulmonary vessels. Signal intensities of perfusion maps on the normal parenchyma were significantly improved (30%) by using B-22956/1, in comparison with perfusion images using gadoteridol (P < 0.01). Many pulmonary angiograms with approximately equal contrast could be obtained even at 22 minutes after the injection of B-22956/1. Our initial results indicate that blood pool agent B-22956/1 may provide opportunities for whole-lung-coverage perfusion mapping and additional high-resolution target angiograms after a single injection.

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Receptor supersensitivity is an important concept for understanding neurotransmitter and receptor dynamics. Traditionally, detection of receptor supersensitivity has been performed using autoradiography or positron emission tomography (PET). We show that use of magnetic resonance imaging (MRI) not only enables one to detect dopaminergic supersensitivity, but that the hemodynamic time course reflective of this fact is different in different brain regions. In rats unilaterally lesioned with intranigral 6-hydroxydopamine, apomorphine injections lead to a large increase in hemodynamic response (cerebral blood volume, CBV) in the striato-thalamo-cortico circuit on the lesioned side but had little effect on the intact side. Amphetamine injections lead to increases in hemodynamic responses on the intact side and little on the lesioned side in the same animals. The time course for the increase in CBV after either amphetamine or apomorphine administration was longer in striatum and thalamus than in frontal cortex. (11)C-PET studies of ligands which bind to the dopamine transporter (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane 1, 5-naphthalnendisulfonate, WIN 35, 428 or CFT) and D2 receptors (raclopride) confirm that there is a loss of presynaptic dopamine terminals as well as upregulation of D2 receptors in striatum in these same animals. Pharmacologic MRI should become a sensitive tool to measure functional supersensitivity in humans, providing a complementary picture to that generated using PET studies of direct receptor binding.

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The purpose of this work was to optimize a technique to measure blood T1 dynamically after contrast agent administration with a high temporal resolution. This technique uses a 90 degrees prepared gradient-echo sequence and has a temporal resolution of one T1 measurement per cardiac cycle. The non-ideal excitation slice profiles on the estimation of T1 were evaluated by theoretical simulations and used to obtain corrected blood T1 values. The technique was validated on phantom and in vivo pig studies, which demonstrated significant improvement on the accuracy of the dynamic T1 measurement method after slice profile correction. This technique may find important applications in studying the dynamic blood T1 after injection of various contrast agents. J. Magn. Reson. Imaging 1999;10:576-581.

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We investigated the regional and temporal changes in cerebral blood volume (CBV), cerebral blood flow (CBF), and vascular transit time in seven mongrel cats during 30 min transient focal ischemia, caused by occlusion of the middle cerebral artery. Dynamic susceptibility contrast magnetic resonance imaging was done at 4.7 T, using fast gradient echo T2* weighted imaging and intravenous injection of gadolinium-BOPTA/Dimeglumine. During occlusion, the areas showing a blood volume change were predominantly within the middle cerebral artery territory and could be divided into areas showing either CBV increases or decreases. The area with decreased blood volume also had decreased blood flow as measured by our flow-based index (p < 0.05) and was located in the central territory of the middle cerebral artery. Peripheral to this region was an area showing increased blood volume but without significant CBF changes (p > 0.05). During reperfusion, the CBF increased in the entire zone showing changes in blood volume during occlusion, and remained significantly elevated until 45 min post-occlusion, while CBV remained elevated in the hyperemic rim for at least 2 h. The presence of a peri-ischemic zone showing flow/volume mismatch identified a region wherein baseline CBF is maintained by means of compensatory vasodilatation, but where the ratio of CBF to CBV is decreased. Dynamic susceptibility contrast magnetic resonance imaging with gadolinium-BOPTA/Dimeglumine may be a valuable technique for the investigation of regional and temporal perturbations of hemodynamics during ischemia and reperfusion.

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The effect of off-resonance irradiation on the water proton NMR signal intensity has been investigated as follows: (a) in the presence of a paramagnetic probe like manganese(II); (b) in the presence of bovine serum albumin (BSA) and two gadolinium(III) complexes, Gd-DTPA and Gd-BOPTA; (c) in the presence of cross-linked BSA and the two above-mentioned gadolinium(III) complexes. The experimental data have been rationalized on the basis of the available theoretical models. The effectiveness of the two complexes as contrast agents for MRI has been predicted. It is shown that contrast agents providing comparable longitudinal and transverse relaxation rate enhancements are those of general interest for off-resonance magnetization transfer-MRI.

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RATIONALE AND OBJECTIVES: The authors assess the effect of weak protein binding on the efficacy of gadolinium chelates as contrast agents for magnetic resonance imaging (MRI). METHODS: Chelates with no (gadopentetate dimeglumine), weak (gadobenate dimeglumine), and strong (B-21326/7) protein binding were compared by in vitro MRI at 2T (spin echo [SE]: repetition time [TR]/echo time [TE] 350/8 mseconds) on solutions in 0.5 mM bovine serum albumin and in rat whole blood, and by in vivo MRI at 2T on rat models of brain tumors (SE TR/TE 350/10 mseconds) and of focal blood-brain barrier disruption (SE TR/TE 400/15 mseconds) after injection of MPP+. Relaxation rate enhancement in the blood of normal rabbits was measured in vivo after administration of contrast agents using IR-Snapshot FLASH. RESULTS: Signal intensity enhancement measured in vitro for whole rat blood 0.1 mM in gadobenate was 142% relative to the same concentration of gadopentetate. Peak signal intensity enhancement in brain tumors was 87% +/- 8% and 64% +/- 5% after 0.1 mmol/kg intravenous administration of gadobenate and gadopentetate, respectively; in MPP+ lesions, the peak signal intensity enhancement was 22% +/- 9%, 32% +/- 7%, and 64% +/- 14% after 0.2 mmol/kg intravenous of gadopentetate, gadobenate, and B-21326/7, respectively. In rabbits, the relaxation enhancement of blood 5 minutes after B-21326/7 and gadobenate administration was 323% and 182%, respectively, relative to the same dose (0.1 mmol/kg intravenous) of gadopentetate. CONCLUSIONS: Weak protein binding can substantially increase the efficacy of gadolinium chelates as general purpose contrast agents for MRI.

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This study tested whether Gd-BOPTA/Dimeg or Gd-DTPA exerts greater relaxation enhancement for blood and reperfused infarcted myocardium. Relaxivity of Gd-BOPTA is increased by weak binding to serum albumin. Thirty-six rats were subjected to reperfused infarction before contrast (doses = 0.05, 0.1, and 0.2 mmol/kg). delta R1 was repeatedly measured over 30 min. Gd-BOPTA caused greater delta R1 for blood and myocardium than did Gd-DTPA; clearance of both agents from normal- and infarcted myocardium was similar to blood clearance; plots of delta R1 myocardium/delta R1 blood showed equilibrium phase contrast distribution. Fractional contrast agent distribution volumes were approximately 0.24 for both agents in normal myocardium, 0.98 and 1.6 for Gd-DTPA and Gd-BOPTA, respectively, in reperfused infarction. The high value for Gd-BOPTPA was ascribed to greater relaxivity in infarction versus blood. It was concluded that Gd-BOPTA/Dimeg causes a greater delta R1 than Gd-DTPA in regions which contain serum albumin.

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The currently prevailing trends in industrial contrast agent research for MRI are discussed. Specific mention is made of contrast agents for liver imaging using both static and delayed procedures, of the potential for blood pool agents and the form such agents may take, and of the ultimate challenge for contrast agent R&D: tissue-targeting in a wider sense to both normal and pathologic tissues.

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This work was conducted to test the hypothesis that contrast-enhanced MRI with hepatocyte-specific contrast agents facilitates quantitation and mapping of diffuse liver diseases such as hepatitis and cirrhosis. Gadobenate dimeglumine (Gd-BOPTA/Dimeg, Bracco SpA, Millano, Italy) is a new paramagnetic hepatocyte-specific contrast agent currently undergoing clinical trials. We have assessed the usefulness of gadobenate dimeglumine for the diagnosis of diffuse liver diseases in a rat model of chemically induced hepatitis. The study was based on the measurements of in vivo liver relaxation times as well as on the acquisition of standard SE images. Acute hepatitis considerably reduced the degree of T1 shortening of liver parenchyma caused by intravenous injection of .25 mmol/kg of gadobenate dimeglumine. Analogously, the enhancement of the MRI signal intensity of the liver of rats with hepatitis observed in T1-weighted spin-echo (SE) images was inferior, in terms of both strength and duration, to that recorded in control rats at doses of .25 mmol/kg and .075 mmol/kg of gadobenate dimeglumine. Our results show that gadobenate dimeglumine-enhanced MR imaging has the potential for visualization of hepatitis and for assessment of liver function. Our conclusions differ from those previously published on this subject by other authors. The reasons that led to differing conclusions are discussed.

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RATIONALE AND OBJECTIVES: We monitored the differences in the first passage of gadobenate dimeglumine through normal and ischemic myocardium with left anterior descending (LAD) coronary artery occlusion in dogs. METHODS: Dynamic multislice images of the heart were taken on a 1.5-T magnetic resonance (MR) imager. In six normal dogs, inversion recovery (IR)-prepared fast gradient-recalled echo (GRE) images were acquired at five doses of gadobenate dimeglumine (0.005-0.1 mmol/kg). First passage of the contrast medium through normal and acutely ischemic myocardium were monitored in seven dogs subjected to LAD coronary artery occlusion. RESULTS: IR-prepared GRE images showed a dose-dependent increase in the signal intensity (SI) of the myocardium. In dogs with LAD coronary artery occlusion, there was a significant increase in the SI of normal myocardium (p < .01) than in ischemic myocardium after injection of 0.025 mmol/kg gadobenate dimeglumine. CONCLUSION: The first-pass dynamics of gadobenate dimeglumine through normal and ischemic myocardium can be monitored with a multislice acquisition using a clinical MR imager and differentiated between normal and ischemic myocardium in dogs.

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PURPOSE: To monitor with fast gradient-echo magnetic resonance (MR) imaging the dynamics of gadolinium benzyloxypropionictetraacetate (gadobenate) dimeglumine on myocardial signal intensity in dogs with critical left circumflex coronary artery stenosis. MATERIALS AND METHODS: Fast gradient-echo MR images were acquired in a short axis of the left ventricle. Two bolus injections of 0.05 mmol/kg gadobenate dimeglumine were administered in the basal state after stenosis and after infusion of 0.5 mg/kg dipyridamole. RESULTS: In the basal state, there was an equivalent increase in signal intensity of normal and hypoperfused myocardium during the first pass. Dipyridamole increased left anterior descending flow (287% +/- 36; P < .05) and decreased left circumflex flow (65% +/- 14; P < .05). The magnitude of signal intensity increase during the second bolus in the hypoperfused region was less than that of normal myocardium (P < .05). Contrast-enhanced images showed the hypoperfused region as smaller than the postmortem measurement (43.8% +/- 3.3; P < .05). CONCLUSION: Contrast-enhanced fast MR imaging in the vasodilated state allows detection of hypoperfused myocardium in the presence of critical coronary stenosis.

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BACKGROUND: The current treatment of many cases of acute myocardial infarction involves the use of thrombolytic agents. Evaluation of this therapy requires determination of the success of reperfusion and assessment of the presence and extent of infarction in the reperfused territory. The present study was designed to simulate in rat models several possible outcomes of reperfusion therapy: (1) successful reperfusion and absence of myocardial infarction, (2) successful reperfusion and presence of myocardial infarction, and (3) unsuccessful reperfusion. The usefulness of contrast-enhanced fast magnetic resonance (MR) imaging in defining the success of reperfusion was investigated. The dynamic effects were examined of low and high doses of gadolinium-BOPTA/dimeglumine (Gd-BOPTA/dimeg) on myocardial signal using MR inversion recovery echo planar imaging (IR-EPI) and gradient recalled echo planar imaging (GR-EPI), respectively. METHODS AND RESULTS: Rats were subjected to one of the following regimens: reperfused reversible myocardial injury (n = 9), reperfused irreversible myocardial injury (n = 9), and occlusive infarction (n = 9). MR echo planar images were acquired every 1 or 2 seconds before, during, and after administration of Gd-BOPTA/dimeg. In all groups, normal myocardial signal was sharply increased on IR-EPI and decreased on GR-EPI at the peak of the bolus, followed by a gradual decline to baseline. In animals subjected to reperfused reversible myocardial injury, normal and previously ischemic regions were indistinguishable during and after the passage of Gd-BOPTA/dimeg. On the other hand, enhancement of reperfused irreversibly injured myocardium was delayed but increased steadily to a higher level than normal myocardium on IR-EPI. The reperfused irreversibly injured myocardium was identified on IR-EPI as a zone of high signal (hot spot). On GR-EPI, signal loss in reperfused irreversibly injured myocardium was significantly less compared with normally perfused myocardium. In animals with occlusive infarctions, there was no change in signal intensity over the ischemic region on either IR-EPI or GR-EPI. Occlusive infarction was identified as zones of either low (cold spot) or high (hot spot) signal compared with normal myocardium, depending on MR pulse sequence and dose of the contrast medium. CONCLUSIONS: The transit of Gd-BOPTA/dimeg monitored by fast MR imaging techniques can be used to distinguish between reperfused reversibly and reperfused irreversibly injured myocardium and between occlusive and reperfused infarctions.

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Ongoing technical improvements in magnetic resonance imaging (MRI) and the development of liver-specific contrast agents are likely to have an impact on the clinical assessment of liver disease. Technical progress towards methods of motion-free MRI and concepts of liver-specific contrast agents are presented. The potential impact of these developments on clinical medicine is discussed.

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The commercial synthetic homopolypeptide polyaspartate (average MW = 30,000, approximately 220 monomers) in solution quantitatively binds up to 40 mol Gd3+ ions per mole of polyaspartate. The water proton relaxivity of the solutions is far higher than that of clinically used or commonly investigated gadolinium(III) complexes. It is shown that polymetallic macromolecular complexes combine the high relaxing efficiency of monometallic macromolecular complexes with the favorable metal/ligand mass ratio of small monometallic complexes.

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