Rüdiger Lawaczeck

Gadolinium neutron capture therapy (GdNCT) of melanoma cells and solid tumors with the magnetic resonance imaging contrast agent gadobutrol

RATIONALE AND OBJECTIVES The therapeutic gain of neutron capture therapy with a neutral macrocyclic gadolinium (Gd) complex (Gadobutrol) was evaluated through in vitro and in vivo studies in a beam of low-energy neutrons. METHODS Neutron irradiation for both the in vitro and in vivo studies was performed in a beam of low-energy neutrons produced by the research reactor of the Hahn-Meitner-Institut, Berlin. Malignant melanoma cells of human origin were irradiated in the presence or absence of Gadobutrol. In vivo irradiation was performed on tumor-bearing nude mice. The tumor site was irradiated subsequent to intratumoral injection of Gadobutrol and compared with irradiation in the absence of the Gd complex. RESULTS In vitro studies showed a Gd-dependent delay of cell proliferation as a consequence of neutron irradiation. In animals, intratumoral administration of the Gd complex at a dose of 1.2 mmol Gd/kg before neutron irradiation results in a significant delay in tumor growth with respect to the control groups. CONCLUSIONS In vitro and in vivo studies showed a therapeutic benefit with the neutral Gd complex and suggest Gd-containing magnetic resonance contrast media are potential candidates for neutron capture therapy. The Gd dose used in the irradiation experiments was four times the presently accepted high dose in clinical magnetic resonance imaging.

New contrast media designed for x-ray energy subtraction imaging in digital mammography.

Rationale and Objectives:In contrast-enhanced dual-energy subtraction imaging 2 images acquired postcontrast media administration at different energies are subtracted to highlight structures hidden in the absence of contrast media. X-ray spectra of the newly developed digital full-field mammography units (GE Senographe 2000 D) are dominated by the emission lines of the Mo or Rh anodes. The K–edge of Zirconium (Zr) is flanked by these 2 emission lines. Thus, the attenuation of Zr should experience a pronounced change of attenuation in parallel with a change of anodes. Under clinically relevant conditions, the contrasting behavior of Zr should be compared with that of other elements having K-edge energies outside the window spanned by the 2 anode emission lines. Methods:Solutions containing the contrasting elements Br, Y, Zr, I, and Gd were investigated for dual-energy subtraction in digital mammography with the 2 anode/filter settings (Mo/Mo and Rh/Rh). These solutions were investigated in phantom studies in the energy range conventionally used in mammography. Additionally, the contrasting behavior of Zr and I was compared in an in vivo study in rats. Results:The sweeping over the K–edge by alternating between the Mo and Rh anodes increases the detection of Zr in energy subtraction imaging at constant high voltage. This procedure does not lead to sufficient contrast enhancement for iodine-based contrast media which become detectable by increasing the high voltage to 40–49 kV. Conclusion:The instrumental and physical data outlined predestine Zr as contrasting element with a high potential for energy subtraction imaging in digital mammography in the energy range conventionally applied.

Pharmacokinetics of contrast media in humans: model with circulation, distribution, and renal excretion.

Aim:To contribute to the understanding of the pharmacokinetics of intravenously administered, renally excreted contrast media with circulation, distribution, and renal excretion providing access to optimized and patient-based administration protocols. Method:Numerical solutions of the pharmacokinetic equations are presented where the physiological parameters (organ volumes, blood flows) and administration parameters (dose, concentration, and velocity) are fixed and the variable parameters (the exchange rates between plasma and interstitium, the rate for renal excretion) are adjusted to results from clinical studies of healthy individuals. Results:Recirculation, organ plasma concentrations, and renal excretion are adequately modeled. With the calculated distribution and renal excretion rates, 3 time periods are discriminated:Mixing period (initial 100 seconds). Bolus decay;Distribution period (about 500 seconds). Volume of distribution approaches a constant value;Equalization period (about 1200 seconds or ≥55 circulations). Ratios of the organ concentrations reach constant values with kidneys, the location of excretion, showing the lowest ratios. Conclusion:The model describes bolus tracking, recirculation, plasma to interstitium distribution, and renal excretion. For known administration parameters, the relevant pharmacokinetic parameters can be achieved from the results of clinical studies. If the arguments are reversed, the pharmacokinetic parameters obtained allow the calculation of personalized administration protocols for computed tomography and magnetic resonance imaging examinations where the 2 initial time periods are essential.

Pharmacokinetic approach for dynamic breast MRI to indicate signal intensity time curves of benign and malignant lesions by using the tumor flow residence time.

ObjectiveThe objective of this study was to evaluate a novel pharmacokinetic approach integrating a tumor model in a whole-body pharmacokinetic model to simulate contrast media-induced signal intensity time curves of breast tumors on dynamic contrast-enhanced magnetic resonance mammography. Materials and MethodsA recently developed, whole-body pharmacokinetic model, which describes the distribution and excretion of renally discharged contrast media, has been expanded by integrating a tumor model. The parameters of the general approach including exchange between plasma and interstitium were set as fixed values; only 2 tumor-specific parameters, blood volume fraction Vblood and blood flow kt, were varied. These parameters were adjusted with regard to signal intensity time course data of histologically verified benign and malignant mass-like breast lesions on clinical magnetic resonance imaging examinations (1.5 T) using 2 different contrast media (gadopentetate dimeglumine and gadoterate meglumine) and 2 application doses (0.1 and 0.2 mmol kg−1 body weight). Thus, measured signal intensity time curves were compared with simulated gadolinium (Gd) concentration time curves calculated by the pharmacokinetic model. ResultsBenign lesions showed continuous signal increase; malignant tumors presented fast initial signal increase followed by washout effect. According to the pharmacokinetic approach, the variation of the Vblood/kt ratio, which defined the tumor flow residence time &tgr;r, led to Gd concentration time curves congruent with the shapes of the measured signal intensity time curves. Low values of &tgr;r were characteristic for malignant tumors, and high values were typical for benign lesions; &tgr;r of 200 seconds best separated malignant from benign tumors. Thus, the dynamic magnetic resonance imaging data can be well approximated by the pharmacokinetic model considering 2 contrast media and application doses. The calculated Gd concentration time curves of 0.1 mmol kg−1 body weight gadopentetate dimeglumine and gadoterate meglumine overlapped for benign lesions; the curve of gadoterate meglumine was by a factor of 0.8 below the curve of gadopentetate dimeglumine for malignant tumors. Doubling the application dose of gadopentetate dimeglumine from 0.1 to 0.2 mmol kg−1 led to an increase in the Gd concentration time curves for benign lesions but not for malignant tumors. High Gd concentrations with values greater than 1 mmol L−1 were calculated in the vessels of the malignant tumors, outside the determined range of the linear relationship between Gd concentration and signal intensity due to saturation effects. ConclusionsOn the basis of this pharmacokinetic model, the contrast media-induced time curves on dynamic contrast-enhanced magnetic resonance mammography can be classified by a single kinetic parameter, the tumor flow residence time &tgr;r, into benign (&tgr;r >200 seconds) and malignant (&tgr;r <200 seconds) curve shapes. Possible clinical application of this model is to create pharmacokinetic maps, displaying tumor flow residence times, for computer-assisted diagnosis, which may be integrated into clinical routine for the diagnosis of breast lesions.

Contrast Media for X-ray and Magnetic Resonance Imaging: Development, Current Status and Future Perspectives.

AbstractOver the last 120 years, the extensive advances in medical imaging allowed enhanced diagnosis and therapy of many diseases and thereby improved the quality of life of many patient generations. From the beginning, all technical solutions and imaging procedures were combined with dedicated pharmaceutical developments of contrast media, to further enhance the visualization of morphology and physiology. This symbiosis of imaging hardware and contrast media development was of high importance for the development of modern clinical radiology. Today, all available clinically approved contrast media fulfill the highest requirements for clinical safety and efficacy. All new concepts to increase the efficacy of contrast media have also to consider the high clinical safety standards and cost of goods of current marketed contrast media. Nevertheless, diagnostic imaging will contribute significantly to the progresses in medicine, and new contrast media developments are mandatory to address the medical needs of the future.

Advantages of Monochromatic X-rays for Imaging

The contrast of X-ray imaging depends on the radiation energy and acquires its maximum value at a certain optimum energy typical for the object under investigation. Usually, higher energies result in reduced contrast, lower energies are absorbed in the object thus having a smaller probability of reaching the detector. Therefore, broad X-ray spectra contain non-optimal quanta to a large extent and deliver images with deteriorated contrast. Since investigations with monochromatic X-rays using synchrotrons are too complex and expensive for routine diagnostic imaging procedures, we propose a simpler approach. A conventional mammography system (Siemens Mammomat 300) with an X-ray tube with a molybdenum anode was supplemented with an X-ray HOPG monochromator (HOPG = Highly Oriented Pyrolytic Graphite) and an exit slit selecting those rays fulfilling Bragg’s condition. The detector is a CCD (Thales TH9570), 4092 x 200 pixels, 54 μm in size. At this slot-scan setup1, measurements have been carried out at 17.5 keV as well as with a polychromatic spectrum with 35 kV tube voltage. The modulation transfer function (MTF) and the detective quantum efficiency (DQE) have been determined from images of a lead bar pattern and flat-field images. Both MTF and DQE depend on orientation (scan or detector direction) for the 17.5 keV monochromatic case. Above 3 mm-1 the DQE values are smaller than those for polychromatic radiation. The contrast yielded by foils of different materials (Al, Cu, Y, Ag) has been studied. In all cases the monochromatic X-rays give rise to about twice the contrast of a polychromatic spectrum.

Comparison of polychromatic and monochromatic x-rays for imaging

Monochromatic X-rays have been proposed for medical imaging, especially in the mammographic energy range. Our previous investigations have shown that the contrast of objects such as lesions or contrast media can be enhanced considerably by using monochromatic X-rays instead of the common polychromatic spectra. Admittedly, only one specific polychromatic spectrum and one monochromatic energy have been compared so far. In this work, we investigated the contrast yielded by a series of different X-ray spectra obtained by varying tube voltage and beam filtering. This resulted in spectra of different mean energies and spectral widths. The objects under examination were aqueous solutions containing different chemical elements such as I, Gd, Dy, Yb, and Bi. A monoenergetic spectrum at 17.5 keV was obtained using a mammographic X-ray tube with a Mo anode and a monochromator equipped with a HOPG crystal. Moreover, we simulated quasi-monoenergetic spectra at different energies and with different widths. As a result, we demonstrated that in many cases spectra with an energetic width of some keV yield an equivalent contrast to monoenergetic radiation at the same energy. Therefore, the advantage in image contrast of monochromatic X-rays at 17.5 keV over narrow-band polychromatic X-ray spectra obtained by appropriate filtering is only slight. Thus, the additional expenditure on a mammography system with HOPG monochromator that can deliver only a small X-ray dose and the unfavorable slot-scan geometry can be avoided. Moreover, we carried out simulations of monochromatic versus polychromatic spectra throughout the whole radiographic energy range. We found advantages in using monochromatic X-rays at higher energies and thicker objects that will justify their application for diagnostic imaging in a number of specific cases.

Contrast Media in CEDM

The basic concept that creates contrast in X-ray images is the different absorption of X-rays by different tissues. For example, dense breast glandular tissue does absorb far more X-rays in comparison to fatty tissue. In many experimental designs, the X-ray absorption of dense breast glandular tissue is similar to that of water. Unfortunately the difference in the X-ray absorption between tissues is very little and hence the similarity between the image contrast of tumorous tissue in comparison to glandular tissue in dense breasts.