MXPA99011508A - Use of intravenous contrast agents and devices for projection mammography - Google Patents

Abstract

The invention relates to the use of intravenous contrast agents for projection mammography and novel devices for carrying out projection mammography. The invention therefore relates to the use of intravenous contrast agents for producing a diagnostic medium for projection mammography. With the additional intravenous administration of contrast agent, projection mammography attains a sensitivity comparable to the most modern methods, such as magnetic resonance tomography (MRT) while having a wider range of applications and avoiding the cost of MRT. This novel method is simple and can be carried out without special inconvenience for the patients. It a) considerably improves sensitivity for demonstrating focal lesions in the mammae and b) provides additional information on the character of previously detected lesions.

Description

USE OF INTRAVENOUS CONTRAST AGENTS FOR PROJECTION MAMMOGRAPHY Description of the invention The invention relates to the use of intravenous contrast agents for projection mammography as well as new devices for projection mammography. STATE OF THE ART Mammography is an X-ray technique established for dozens of years and continuously perfected for the early detection, verification, roentgenological characterization and localization of breast tumors. In many aspects it has not been matched in its capacity and availability for the patients. The biggest disadvantage lies in an imperfect detection sensitivity for tumors of smaller size and without detectable microcal. From the beginning, we tried to apply contrast agents to improve projection mammography. For this purpose, suitable preparations were introduced into the galactoform ducts and the distribution of these in the chest was used to detect and characterize lesions. A summary is found in the work R Bj0rn-Hansen: Contrast-mammography, Brit. J. Radiol. 38, 947-951, 1965. The technique is also known as galactography. The contrast is achieved by concentrated contrast agents containing iodine (> 100 mg iodine / ml). In addition, contrast agents have been injected directly into suspicious or tumorous lesions of the breast, either to characterize them (for example B. Lehto M. and Mathiesen TL: Adenography: An ancillary diagnostic method of circumscribed lesions of the breast with a positive contrast agent, Breast Dis, 6, 259-268, 1993) or to mark them (eg Raininko R., Linna MI, Rasanen O .: Preoperative localization of nonpalpable breast tumors, Acta Chir Scand, 142, 575-578, 1976). In both cases commercial undiluted contrast agents are used directly. The very rare exception is the intravenous administration of X-ray contrast agents for the representation of parenchymal processes on the projection radiograph. It is only successful if a tissue or an organ actively concentrates the contrast agent. For this there are two examples to date: the representation of the parenchyma of the healthy kidney by means of the usual urográficos today, and the representation of the parenchyma of the healthy liver and spleen by dense emulsions or suspensions to the X-rays. Both methods are no longer use (liver, spleen) or only in exceptional cases (kidney). It has never been successful in taking advantage of intravenously administered roentgenological contrast agents to directly contrast tumors of relevant size on the projection radiograph. Computed tomography and in particular magnetic resonance tomography are known for their much higher measurement sensitivity with respect to contrast agents. However, it was surprising that with both techniques chest tumors could be detected with great certainty after an intravenous injection of contrast agent (Gisvold JJ, Karsell PR, Reese EC: Clinical evaluation of computerized tomographic mammography.) Mayo Clin Proc 52, 181- 185, 1977; Teifke A., Schweden F., Cagil H., Kanczor HU, Mohr W., Thelen M.: Spiral-Computertomographie der Mamma, Fortschr, Rontgenstr 161, 495-500, 1994, Heywaqng SH, Hahn D. , Schmidt H., Krischke I., Eiermann W., Bassermann R., Lissner J.: MR imaging of the breast using Gadolinium DTPA, J Comp Ass Tomogr 10, 199-204, 1986). Even after the intensification of the contrast of breast tumors has been published by intravenous administration of contrast agents in CT, the detection sensitivity of projection mammography has been considered too low with respect to contrast agents that have been considered too low. contain iodine to be able to take advantage of this detectable effect on CT in mammography. Therefore, the usefulness for this application of the contrast agents containing bromine is even less likely., which are known to be less dense to X-rays, or solutions of metal chelates only available in low concentrations. Fritz S.L., Chang C.H.J. and Livingston WH: (Scatter / primary ratios for X-ray spectra modified to enhance iodine contrast in screen-film mammography, Med Phys 10, 866-870, 1983) therefore investigate the question whether a variety of physical measurements can be generated by radiation quality more suitable for the absorption spectrum of iodine. The results of his work are still considered unsatisfactory, but he is given certain possibilities of an additional optimization to the roentgenological spectrum. In the mid-1980s an attempt was made to apply digital subtraction angiography (DSA) with intravenous injection of contrast agents. However, the process has not been achieved because the reliability and sensitivity are too low, and in each case additional auscultation is required (Dean PB, Sickles EA: Invest Radiol 20, 698-699, 1985) . The aforementioned methods have advantages with respect to conventional projection mammography, but also significant disadvantages such as high costs and limited availability, absence of detection of the microcal, important for the diagnosis of tumors, a reduced spatial resolution, a time of prolonged auscultation, difficult access for biopsies and greater exposure to radiation. Even though not every disadvantage is true for each technique, nowadays only a very small part of the MR patients are applied, and even more so the CT, the DSA practically is not used at all for the verification of breast tumors. . Due to the almost universal availability, low costs and in many aspects high capacity, an improvement of the projection mammography established with a view to the safe detection of tumors is of significant significance. In this sense, many tests have already been carried out. In particular, the image recording technique and the film material used were optimized; Xeroradiography was tested. New receiver systems and digitalization promise more progress. However, as far as can be established, projection mammography is clearly below the sensitivity of the best current method, the intensified contrast magnetic resonance tomography. Description of the invention It was now discovered in a totally surprising way that it is possible to improve the projection radiography, known for its insensitivity to contrast agents, in the special case of projection mammography by intravenous administration of contrast agents, despite that the contrast agents are strongly diluted during their path through the heart and the lung and that there is no known active concentration in the tumomes of the chest. Accordingly, the invention relates to the use of intravenous contrast agents to produce a diagnostic agent for projection mammography. Through the additional administration of intravenous contrast agents, projection mammography achieves a sensitivity comparable to that of more modern processes such as magnetic resonance tomography (MRT) while having a significantly more diverse applicability and saving the costs of MRT. . The new method can be carried out in a simple manner and without subjecting patients to exceptional discomfort, and results in a considerable improvement a) in the sensitivity for the detection of focal lesions in the chest, and b) additional information on the character of previously detected injuries. The application according to the invention can be carried out, for example as follows with currently available apparatuses and means, as long as the apparatuses are operated with a low energy of the rays, as is usual in projection marnography. The method of measurement of preference is carried out as follows: 1) A normal mammogram is taken (precontrast image) 2) The patient is given a conventional urological roentgenological contrast agent, in a dose of approximately 0.5 g to 1.5 g of iodine / kg of body weight rapidly injected or infused intravenously. 3) From 30 seconds to 1 minute after the end of the injection, a second mammogram is taken (postcontrast image). Eventually more images are taken up to approximately 5 minutes after the end of the injection, which if necessary can give additional information about the characteristics of the lesion. Appliances and device settings of less than 50 kV are suitable for the application according to the invention; it is preferred to use radiation corresponding to 20 kV to 40 kV, very particularly a light energy of 25 kV to 35 kV is preferred. For the application according to the invention, all the compounds commonly used for the preparation of water-soluble urographic contrast agents are suitable. By way of example we will mention: meglumin or diatrizoate of lysine, iotalamato, ioxitalamato, iopromide, iodhexol, iomeprol, iopamidol, ioversol, iobitridol, iopentol, iotrolan, iodixanol and ioxilan (INN). However, it is also possible to use compounds that do not contain iodine, for example: 1. Bromine-containing contrast agents as an image-generating element, 2. Contrast agents containing elements of atomic numbers 34, 42, 44- 52, 54-60, 62-79, 82 or 83 as a generator of the image, 3. Contrast agents containing chelated compounds of atomic number elements 56-60, 62-79, 82 or 83 as a generator element of the image. Accordingly, the invention also relates to the use of these compounds without iodine. Today's roentgenological contrast agents are excellently suited for the described process. It was surprisingly discovered that unlike almost any other roentgenological method it is possible to completely or partially exchange the iodine element with the bromine element in the projection mammography.

Even though this has been discussed in the past, it has not been satisfactory in any roentgenological method due to the markedly lower absorption of bromine radiation compared to iodine. In this, projection mammography represents an exception. It is a surprising novel application for, for example, the compounds described in EP 0 118 348 A1. In addition, secretable and acceptable contrast agents based on other elements, molecular structures and the like are also suitable for use according to the invention. supramolecular contrast generators. As contrast generating elements, those with the atomic numbers 34, 42, 44-60, 62-79, 82 or 83 are particularly suitable. The contrast-generating elements can be linked to organic molecules covalently or can be in the form of complexes. or be integrated into macromolecular structures. Especially advantageous are substances with a molecular weight of 10,000 to 80,000 D. In addition, the individual molecules of the contrast agents can be a component part of larger structures such as associations, liposomes, emulsion drops and micro and nanoparticles (Parvez Z., Moneada R., Sovak M., eds .: Contrast Media: Biological Effects and clinical application, Vol III, CRC Press, Boca Raton, Florida 1987, 73-130). The preparation is carried out conventionally in physiologically acceptable vehicles, preferably water, with the use of conventional auxiliary substances such as stabilizers (for example complexes, complexing agents, antioxidants), regulators (for example tris, citrate, bicarbonate). , emulsifiers and substances for the adjustment of osmolality and electrolyte content, as required. Contrast agents with concentrations of 100 mg iodine / ml to 500 mg iodine / ml are preferred, particularly non-ionic roentgenological contrast agents with 200 mg iodine / ml at 400 mg iodine / ml, or with a corresponding roentgenological density in the case of choosing another radiation absorbing element. The agent can be applied in a dose of 150 to 1500 mg iodine / kg body weight (KG). In the use according to the invention of bromine-containing compounds, a concentration of 100 to 500 mg bromine / ml in the contrast agent is preferred. The applicable dose is 100 to 1500 mg bromine / kg body weight. In the use according to the invention of compounds of the elements with atomic numbers 34, 42, 44-52, 54-60, 62-79, 82 or 83, a concentration of 10 mmoles to 2 mols / 1 in the agent is preferred. of contrast in relation to the element generating the image. The applicable dose is 0.1 to 2 mmoles / kg of body weight (in relation to the image generating element). The range of 0.2 to 0.6 mmol / kg of body weight is preferred. In the use according to the invention of chelated compounds of elements with atomic numbers 56-60, 62-79, 82 or 83, a concentration of 10 mmoles to 2 mols / 1 in the contrast agent with respect to the generating element is preferred. from image. The applicable dose is 0.1 to 2 mmoles / kg of body weight (with respect to the image generating element). The range of 0.2 to 0.6 mmol / kg of body weight is preferred. A very advantageous variant of the use of intravenous contrast projection mammography according to the invention is related to the subtraction technique that until now has not been introduced in projection mammography. However, the corresponding processes have given very good results in angiography. However, local concentrations of iodine are also required on angiography. (in the blood) considerably greater than those that can be achieved in breast tumors. In this it was not possible to foresee the possibility of applying this technique to check small lesions. Therefore the process is based on the use for the mamomagraphy of digital image receptors, which must have a sufficiently good local resolution for this method of auscultation. In order to achieve this resolution necessary for mammography in the digital image, it is therefore possible to work with digital image receptors with small pixel sizes, or to use digital image receivers in combination with the direct radiographic intensification technique. Through the combined application of the intensification technique with digital image receivers, both the resolution of the contrast and the local resolution are significantly improved. By this, the verification of small lesions is considerably facilitated. The process is substantially based on the following stages: 1) A normal mammogram is taken (precontrast image). The data is stored. 2) The patient is rapidly injected intravenously with a suitable contrast agent in a sufficient dose. 3) After 30 seconds after the end of the injection application, one or more mammograms are taken and stored. 4) The data obtained according to (1) is correlated with the data obtained according to (3) (preferably subtracted) and the result is correspondingly intensified and issued as an image. 5) Eventually, data are calculated and represented separately with respect to the speed and scope of the increment of the contrast agent, and with respect to the kinetics of the levigation process. Accordingly, the invention also relates to a device for projection mammography characterized by sufficient local resolution for mammographic auscultation. This sufficient local resolution is achieved either directly through the resolution capability of the digital image receiver or through the coupling of the digital image receiver with the direct radiographic intensification technique. In addition, the device comprises at least one storage device for the precontrast image, at least one storage device for the postcontrast image, at least one computing unit for the correlation (in particular subtraction) of the various images and a device output for the calculated mammogram. Apart from the correlation of temporally successive images or data sequences, it is also convenient to correlate images that were produced with different radiation energy. For example, in the case of the use according to the invention of compounds having bromine, it is possible to carry out a tap with a radiation energy of e = = 35 kV and a tap with a radiation energy of e2 = 25 kV , and correlate with one another the stored images, in particular subtract one from another. In this case, a suppression of the normal tissue structures is also achieved in favor of the contrast-generating element supplied intravenously, since the radiation absorption of the tissue differs from that of the contrast agent at the selected energies. By means of a repeated measurement, the temporal development of the concentration of the contrast agent with a device of this nature can also be detected and evaluated. Accordingly, another object of the invention is a device for projection mammography characterized by at least one storage device for a power take-up Si of the rays, at least one storage device for a power take-off e2 of the rays, at least one computer unit to correlate the various images and an output device for the calculated mammogram.

In mammography of classical projection, only one breast is heard in each case. To limit the necessary amount of contrast agent it is convenient in the case of the application according to the invention to auscultate both breasts simultaneously. To date there are no known devices that allow auscultation of this kind. Accordingly, devices of the invention are also object of the invention, characterized in that they allow the simultaneous auscultation of both breasts. EXEMPLARY EMBODIMENTS The following examples should clarify the object of the invention without limiting it to them. Example 1: studies on phantoms Solutions of contrast agents containing bismuth, iodine and bromine ((4S) -4- (ethoxybenzyl) 3,6,9-tris (carboxy-methyl-ethyl) -3,6,9-triaza- undecanic, bismuth complex, disodium salt, iotrolan (INN), or N-cetyl-N, N, N-trimethylammonium bromide) at a concentration of 9.8 mg Bi / ml, 6 mg iodine / ml, or 3.8 mg Br / ml on 2% agar. The agar gels are cut into layer thicknesses of 3-mm, 5 mm or 10 mm. The gels containing the contrast agent as well as a control gel with 2.8 mg NaCl / ml are integrated into a 5 cm thick agar block. The totality of the phantom is subjected to roentgenological radiation at 28 kV and 63 mA, which corresponds to a mammogram, since the roentgenological radiation has to cross in each case approximately 4 cm to 5 cm of free agar of contrast agent and 3 mm to 10 mm of agar containing contrast agent. Result: Even agar pieces of only about 3 mm thick containing contrast agent can be detected well. Surprisingly, bromine is approximately twice as effective as iodine at equimolar concentration; the bisnuto is more than three times more effective than the iodine (figure 1). Figure 1 shows a roentgenological image at 28 kV, 63 mA of an agar phantom having embedded agar blocks containing contrast agent: left row 5 mm thick, center row 10 mm thick, right row 3 mm thick thickness. The blocks in the top row contain 3.8 mg of bromine / ml, those in the middle row 6 mg iodine / ml, those in the bottom row 9.8 mg Bi / ml. The block with NaCl can not be seen. Example 2: Mammography of intravenous contrast agent In one patient, a mammary carcinoma of 1.5 cm by 0.8 cm in size based on structures, microcal and biopsy was mammographically proven. Preoperatively we have to investigate multifocality; for this purpose the patient is given a la. permanent cannula in the vein of the left arm (V. cubitalis). Projection mammography is repeated before administration of the contrast agent. Immediately after the native intake, the infusion of 3 ml / kg of Ultravist®-300 (Schering AG, Berlin, active substance: Iopromid (INN) at a rate of 3 ml / sec. Is started by means of an automatic injector. The first image taking after the administration of the contrast agent takes place 1 minute after the end of the infusion.The position of the patient and the image recording device remain absolutely unchanged during this time interval, as well as the conditions of the capture with 28 kV of bulb tension, and 63 mAs.The images after the injection of the contrast agent show a substantially enhanced area of contrast agent absorption compared to the tissue defined as the tumor area prior to administration of the contrast agent. Contrast agent, but no other focuses separate from concentration in the chest.

Claims (17)

1. CLAIMS Use of intravenous contrast agents to produce a diagnostic agent for projection mammography.
2. Use of an agent according to claim 1, characterized in that the intravenous contrast agent contains iodine as a contrast generating element.
3. Use of an agent according to claim 1, characterized in that the intravenous contrast agent contains bromine as a contrast generating element.
4. Use of an agent according to claim 1, characterized in that the intravenous contrast agent contains a compound of the elements with atomic numbers of 34, 42, 44-52, 54-60, 62-79, 82 or 83.
5. Use of an agent according to claim 1, characterized in that the intravenous contrast agent contains a metallic chelate of the elements with atomic numbers of 56-60, 62-79, 82 or 83.
6. Use of an agent according to claim 1, characterized in that the intravenous contrast agent has a molecular weight of 10,000 to 80,000 D.
7. Use of an agent according to claim 1, characterized in that the contrast agent exists in structures of higher molecular weight.
8. Use of an agent according to claim 7, characterized in that the intravenous contrast agent exists in the form of associations of molecules, liposomes, nano- or microparticles.
9. Use of intravenous contrast agents according to claim 1, characterized in that they exist in a roentgenological density corresponding to 100 mg of iodine / ml to 500 mg of iodine / ml.
10. Use of intravenous contrast agents according to claim 2, characterized in that they exist in a concentration of 100 mg of iodine / ml to 500 mg of iodine / ml.
11. Use of intravenous contrast agents according to claim 2, characterized in that they are administered in a dose corresponding to 150 mg of iodine / kg to 1500 mg of iodine / kg of body weight.
12. Use of intravenous contrast agents according to claim 3, characterized in that they exist in a concentration of 100 mg of bromine / ml to 500 mg of bromine / ml.
13. 13. Use of intravenous contrast agents according to claim 3, characterized in that they are administered in a dose corresponding to 150 mg of bromine / kg to 1500 mg of bromine / kg of body weight.
14. 14. Use of intravenous contrast agents according to claim 4, characterized in that they exist in a concentration of 10 mmol to 2 mol / l.
15. 15. Use of intravenous contrast agents according to claim 4, characterized in that they are applied in a dose of 0.1-2 mmol / kg of body weight.
16. 16. Use of intravenous contrast agents according to claim 5, characterized in that they exist in a concentration of 10 mmol / l to 2 mol / l.
17. 17. Use of intravenous contrast agents according to claim 5, characterized in that they are applied in a dose of 0.1-2 mmol / kg of body weight.