Generation of artificial contrast radiological images

Abstract

FIELD OF THE DISCLOSURE The present disclosure relates to the technical field of generating artificial contrast-enhanced radiological images.

Description

[Technical Field]

[0001] FIELD OF THE DISCLOSURE The present disclosure relates to the technical field of generating artificial contrast-enhanced radiological images. [Background technology]

[0002] WO 2019 / 074938 discloses a method for reducing the amount of contrast agent in the production of radiological images with the aid of an artificial neural network.

[0003] In the disclosed method, the first step is to create a training dataset that includes, for each of a number of individuals, i) original radiographic images (zero contrast images), ii) radiographic images after administration of a low dose of contrast agent (low contrast images), and iii) radiographic images after administration of a standard dose of contrast agent (full contrast images).

[0004] In a second step, the artificial neural network is trained to predict, for each individual in the training dataset, an artificial radiographic image showing the area imaged after a standard dose of contrast agent based on the original image and the image after a low dose of contrast agent. The radiographic image measured after the standard dose of contrast agent serves as a reference (true value) in the training in each case.

[0005] In the third step, the trained artificial neural network can be used to predict, for a new person, an artificial radiographic image showing the area as if a standard dose of contrast had been administered, based on the original image and the radiographic image after the administration of a low dose of contrast.

[0006] The method disclosed in WO 2019 / 074938 has drawbacks.

[0007] For example, training an artificial neural network requires training data, which is generated by performing a large number of radiological examinations on a large number of people.

[0008] The artificial neural network disclosed in WO 2019 / 074938 is trained to predict radiological images following administration of a standard dose of contrast agent. The artificial neural network is not configured or trained to predict radiological images following administration of doses of contrast agent that are lower or higher than the standard dose of contrast agent. The method described in WO 2019 / 074938 could, in principle, be trained to predict radiological images following administration of doses of contrast agent that differ from the standard dose, but this would require additional training data and further training. [Brief explanation of the drawings]

[0009] [Figure 1] [Figure 2] [Figure 3] [Figure 4] [Figure 5] [Figure 6] [Figure 7] [Figure 8] [Figure 9] [Figure 10] [Figure 11] [Figure 12] DISCLOSURE OF THE INVENTION

[0010] It would be desirable to be able to generate radiological images with varying contrast enhancement without having to generate training data for each individual contrast enhancement or train an artificial neural network. Furthermore, it would be desirable to be able to generate radiological images with varying contrast enhancement using a traceable, deterministic process for varying contrast enhancement. This would facilitate the approval and use of corresponding medical procedures while minimizing false negative and false positive results. Machine learning methods use statistical models but are typically based on a limited selection of training data, limiting their generalizability. Furthermore, it would be desirable to be able to generate radiological images with varying contrast enhancement using a wide variety of contrast agents. Furthermore, it would be desirable to be able to use a method for generating radiological images with varying contrast enhancement using a wide variety of different contrast agents, regardless of their physical, chemical, physiological, or other properties.

[0011] These and other objects are achieved by the subject matter of the independent claims. Preferred embodiments of the present disclosure can be found in the dependent claims, the description and the drawings.

[0012] Thus, the present invention provides, in a first aspect, receiving or generating a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; receiving or generating a second representation in frequency space or real space of the examination region of the subject after administration of a second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; generating a weighted third representation, optionally including frequency dependent weighting of the third representation; generating a fourth representation by adding the optionally weighted third representation multiplied by α to the first representation or the second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; outputting and / or storing the fourth representation of the inspection area in real space and / or transmitting the fourth representation of the inspection area in real space to another computer system; A computer-implemented method for generating a composite contrast-enhanced radiological image is provided, comprising the steps of:

[0013] The present disclosure further comprises: a processor, and a memory storing an application program configured to perform operations when executed by a processor, the operations being receiving or generating a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; receiving or generating a second representation in frequency space or real space of the examination region of the subject after administration of a second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; Optionally, generating a weighted third representation generated by applying a frequency dependent weighting to the third representation; generating a fourth representation by adding the optionally weighted third representation multiplied by α to the first representation or the second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; Outputting and / or storing the fourth representation of the inspection area in real space and / or transmitting the fourth representation of the inspection area in real space to another computer system.

[0014] The present disclosure further provides a computer program loadable into the working memory of a computer system, the computer program being operable to receiving or generating a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; receiving or generating a second representation in frequency space or real space of the examination region of the subject after administration of a second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; Optionally, generating a weighted third representation generated by applying a frequency dependent weighting to the third representation; generating a fourth representation by adding the optionally weighted third representation multiplied by α to the first representation or the second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; outputting and / or storing the fourth representation of the inspection area in real space and / or transmitting the fourth representation of the inspection area in real space to another computer system.

[0015] The present disclosure further comprises: receiving or generating a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; receiving or generating a second representation in frequency space or real space of the examination region of the subject after administration of a second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; Optionally, generating a weighted third representation generated by applying a frequency dependent weighting to the third representation; generating a fourth representation by adding the optionally weighted third representation multiplied by α to the first representation or the second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; outputting and / or storing the fourth representation of the inspection area in real space and / or transmitting the fourth representation of the inspection area in real space to another computer system; The present invention provides the use of a contrast agent in a radiological examination method comprising:

[0016] The present disclosure further comprises: receiving or generating a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; receiving or generating a second representation in frequency space or real space of the examination region of the subject after administration of a second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; Optionally, generating a weighted third representation generated by applying a frequency dependent weighting to the third representation; generating a fourth representation by adding the optionally weighted third representation multiplied by α to the first representation or the second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; A contrast agent is provided for use in a radiological examination method, comprising outputting and / or storing a fourth representation of the examination region in real space and / or transmitting the fourth representation of the examination region in real space to another computer system.

[0017] The present disclosure further provides a kit including a computer program product and an imaging agent, the computer program product including a computer program loadable into a working memory of a computer system, the computer program being operable to receiving or generating a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; receiving or generating a second representation in frequency space or real space of the examination region of the subject after administration of a second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; Optionally, generating a weighted third representation generated by applying a frequency dependent weighting to the third representation; generating a fourth representation by adding the optionally weighted third representation multiplied by α to the first representation or the second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; outputting and / or storing the fourth representation of the inspection area in real space and / or transmitting the fourth representation of the inspection area in real space to another computer system.

[0018] The subject matter of the present disclosure will be elucidated in more detail below, without distinguishing between the subject matter (method, computer system, computer program (product), use, contrast agent used, kit). The elucidation that follows below is intended to apply equally to all subject matter, regardless of the context (method, computer system, computer program (product), use, contrast agent used, kit) in which the subject matter appears.

[0019] When steps are described in a certain order in this specification or in the claims, this does not necessarily mean that the disclosure is limited to the order described. Instead, steps may be performed in a different order or performed in parallel with one another, except where one step builds upon another step and therefore requires that the step that builds upon the previous step be performed next (although this will be made clear in each individual case). Therefore, the order described constitutes a preferred embodiment.

[0020] In some parts of this specification, the invention will be more particularly elucidated with reference to the drawings. The drawings show particular embodiments having particular features and combinations of features, which are intended primarily for illustrative purposes, and the invention should not be understood as being limited to the features and combinations of features shown in the drawings. Furthermore, statements made in the description of the drawings with respect to features and combinations of features are intended to be generally applicable, i.e., applicable to other embodiments, and not limited to the embodiments shown.

[0021] The present disclosure describes a means for generating one or more artificial radiological images based on at least two representations of an examination area of ​​an object after adding / administering / using various amounts of contrast agent, which can vary the contrast between areas without contrast agent and areas with contrast agent.

[0022] A "test subject" is typically a living organism, preferably a mammal, most preferably a human.

[0023] An "examination area" is a part of an object under examination, for example an organ, part of an organ, multiple organs, or another part under examination.

[0024] For example, the examination area may be the liver, kidney, heart, lung, brain, stomach, bladder, prostate, intestine, or parts thereof, or other parts of a mammalian (eg, human) body.

[0025] In one embodiment, the examination area comprises a liver or a part of a liver, or the examination area is a liver or a part of a liver of a mammal, preferably a human.

[0026] In a further embodiment, the examination area comprises a brain or part of a brain, or the examination area is a brain or part of a brain of a mammal, preferably a human.

[0027] In a further embodiment, the examination region comprises a heart or a part of a heart, or the examination region is a heart or a part of a heart of a mammal, preferably a human.

[0028] In a further embodiment, the examination region comprises the thorax or a portion of the thorax, or the examination region is the thorax or a portion of the thorax of a mammal, preferably a human.

[0029] In a further embodiment, the examination area comprises a stomach or part of a stomach, or the examination area is a stomach or part of a stomach of a mammal, preferably a human.

[0030] In a further embodiment, the examination area comprises a pancreas or a part of a pancreas, or the examination area is a pancreas or a part of a pancreas of a mammal, preferably a human.

[0031] In a further embodiment, the examination area comprises a kidney or part of a kidney, or the examination area is a kidney or part of a kidney of a mammal, preferably a human.

[0032] In a further embodiment, the examination region comprises one or both or part of the lungs of a mammal, preferably a human.

[0033] In a further embodiment, the examination area comprises a breast or a portion of a breast, or the examination area is a breast or a portion of a breast of a female mammal, preferably a human female.

[0034] In a further embodiment, the examination area comprises the prostate gland or a portion of the prostate gland, or the examination area is the prostate gland or a portion of the prostate gland of a male mammal, preferably a human male.

[0035] The examination region, also called the field of view (FOV), is the volume that is imaged, especially in a radiological image. The examination region is typically defined by a radiologist, for example, on a localizer image. Of course, the examination region can alternatively or additionally be defined in an automated manner, for example, based on a selected protocol.

[0036] A radiological examination is performed on the examination area.

[0037] "Radiology" is a branch of medicine that utilizes electromagnetic and mechanical waves (including, for example, ultrasound) for diagnostic, therapeutic, and / or scientific purposes. Ionizing radiation, such as x-rays, gamma rays, and electron beams, is also used. Because diagnostic imaging is an important application, other imaging modalities, such as ultrasound and magnetic resonance imaging (magnetic resonance imaging), are also considered radiology, even though they do not use ionizing radiation. Thus, the term "radiology" in the context of this disclosure encompasses, among other modalities, computed tomography, magnetic resonance imaging, and ultrasound.

[0038] In one embodiment of the present disclosure, the radiological examination is a magnetic resonance imaging examination.

[0039] In a further embodiment, the radiological examination is a computed tomography examination.

[0040] In a further embodiment, the radiological examination is an ultrasound examination.

[0041] In radiological examinations, contrast agents are commonly used for imaging.

[0042] A "contrast agent" is a substance or mixture of substances that enhances the depiction of bodily structures or functions in a radiological examination.

[0043] In computed tomography, iodine-containing solutions are typically used as contrast agents. In magnetic resonance imaging (MRI), superparamagnetic substances (e.g., iron oxide nanoparticles, superparamagnetic iron platinum particles (SIPP)) or paramagnetic substances (e.g., gadolinium chelates, manganese chelates) are typically used as contrast agents. In ultrasound examinations, liquids containing gas-filled microbubbles are typically administered intravenously.Examples of contrast agents can be found in the literature (e.g., ASL Jascinth et al.: Contrast Agents in Computed Tomography: A Review, Journal of Applied Dental and Medical Sciences, 2016, vol. 2, issue 2, 143-149; H. Lusic et al.: X-ray-Computed Tomography Contrast Agents, Chem. Rev. 2013, 113, 3, 1641-1666; https: / / www.radiology.wisc.edu / wp-content / uploads / 2017 / 10 / contrast-agents-tutorial.pdf, MR Nouh et al.: Radiographic and magnetic resonance contrast agents: Essentials and tips for safe practices, World J Radiol. 2017 Sep. 28; 9(9): 339-349; LC Abonyi et al.: Intravascular Contrast Media in Radiography: Historical Development & Review of Risk Factors for Adverse Reactions, South American Journal of Clinical Research, 2016, vol. 3, issue 1, 1-10; ACR Manual on Contrast Media, 2020, ISBN: 978-1-55903-012-0; A. Ignee et al.: Ultrasound contrast agents, Endosc Ultrasound. 2016 Nov-Dec; 5(6): 355-362).

[0044] MRI contrast agents exert their effects during MRI scans by altering the relaxation time of the tissues into which they are incorporated. They can be divided into two groups: paramagnetic and superparamagnetic. Both groups of agents contain unpaired electrons, which induce a magnetic field around individual atoms or molecules. Superparamagnetic contrast agents primarily cause a shortening of T2, while paramagnetic contrast agents primarily cause a shortening of T1. The effect of contrast agents is indirect, as they do not emit a signal themselves but merely affect the intensity of the signal in their vicinity. An example of a superparamagnetic contrast agent is iron oxide nanoparticles (SPIO, superparamagnetic iron oxide). Examples of paramagnetic contrast agents are gadolinium chelates such as gadopentetate dimeglumine (trade name: Magnevist®, etc.), gadoteric acid (Dotarem®, Dotagita®, Cyclolux®), gadodiamide (Omniscan®), gadoteridol (ProHance®), gadobutrol (Gadovist®), gadopiclenol (Elucirem, Vueway), and gadoxetic acid (Primovist® / Eovist®).

[0045] In one embodiment, the radiological examination is an MRI examination in which an MRI contrast agent is used.

[0046] In a further embodiment, the radiological examination is a CT examination in which a CT contrast agent is used.

[0047] In a further embodiment, the radiological examination is a CT examination in which an MRI contrast agent is used.

[0048] The generation of the artificial radiation image with varied contrast enhancement is based on at least two representations of the examination region, a first representation and a second representation.

[0049] The first and second representations are the results of a radiological examination. The first and second representations are preferably measured radiological images or generated based on measured radiological images. The first and / or second representations may each be MRI, CT, ultrasound and / or other radiological images.

[0050] The first representation represents the examination region without contrast agent or after administration of a first amount of contrast agent. Preferably, the first representation represents the examination region without contrast agent.

[0051] The second expression represents the examination area after administration of a second amount of contrast agent. The second amount is greater than the first amount (which, as mentioned above, may be zero). The expression "after administration of a second amount of contrast agent" should not be understood as meaning that the first and second amounts are added together in the examination area (unless the first amount is zero). Thus, the expression "represents the examination area after administration of the (first or second) amount" should rather be understood as meaning "the expression represents the examination area using the (first or second) amount" or "the expression represents the examination area including the (first or second) amount."

[0052] In one embodiment, both the first amount and the second amount of contrast agent are less than a standard dose.

[0053] In a further embodiment, the second amount of imaging agent corresponds to a standard dose.

[0054] In a further embodiment, the first amount of contrast agent is equal to zero and the second amount of contrast agent is less than a standard dose.

[0055] In a further embodiment, the first amount of contrast agent is equal to zero and the second amount of contrast agent corresponds to a standard dose.

[0056] The standard dose is typically the amount recommended by the manufacturer and / or distributor of the contrast agent and / or the amount permitted by a regulatory agency and / or the amount specified in the package insert for the contrast agent.

[0057] For example, the standard dose of Primovist® is 0.025 mmol of Gd-EOB-DTPA disodium per kg of body weight.

[0058] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium(III) 2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetic acid (also known as gadolinium-DOTA or gadoteric acid).

[0059] In a further embodiment, the contrast agent is a gadolinium(III) ethoxybenzyldiethylenetriaminepentaacetic acid (Gd-EOB-DTPA) containing agent, preferably the contrast agent is a gadolinium(III) ethoxybenzyldiethylenetriaminepentaacetic acid (also known as gadoxet acetate) disodium salt containing agent.

[0060] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium(III) 2-[3,9-bis[1-carboxylato-4-(2,3-dihydroxypropylamino)-4-oxobutyl]-3,6,9,15-tetrazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-6-yl]-5-(2,3-dihydroxypropylamino)-5-oxopentanoate (also known as gadopiclenol) (see, e.g., WO 2007 / 042504 and WO 2020 / 030618 and / or WO 2022 / 013454).

[0061] In one embodiment of the present disclosure, the imaging agent is an agent comprising dihydrogen[(±)-4-carboxy-5,8,11-tris(carboxymethyl)-1-phenyl-2-oxa-5,8,11-triazatridecan-13-oate(5-)]gadolinate(2-) (also known as gadobenic acid).

[0062] In one embodiment of the present disclosure, the imaging agent is a tetragadolinium [4,10-bis(carboxylatomethyl)-7-{3,6,12,15-tetraoxo-16-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]-9,9-bis({[({2-[4,7,10-tris-(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate (also referred to as gadoquatrane)-containing agent (see, e.g., J. Lohrke et al.: Preclinical Profile of Gadoquatrane: A Novel Tetrameric, Macrocyclic High Relaxivity Gadolinium-Based Contrast Agent. Invest Radiol., 2022, 1, 57(10): 629-638; see International Publication No. 2016193190).

[0063] In one embodiment of the present disclosure, the imaging agent is a compound of formula (I) 3+ complex

[0064] [ka] (I)

[0065] (Wherein, Ar is

[0066] [ka] and [ka] is a group selected from # is the connection to X, X is CH2, (CH2)2, (CH2)3, (CH2)4, and *-(CH2)2-O-CH2- # is a group selected from * is the link to Ar, # is the linkage to the acetate residue, R 1 , R 2 and R 3 are each independently a hydrogen atom or a group selected from an alkyl group having 1 to 3 carbon atoms, -CHOH, -(CH)OH, and -CHOCH; R 4 is a group selected from an alkoxy group having 2 to 4 carbon atoms, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 is a hydrogen atom, and R 6 is a hydrogen atom, Or, it is a drug containing its stereoisomer, tautomer, hydrate, solvate or salt, or a mixture thereof.

[0067] In one embodiment of the present disclosure, the imaging agent is a compound of formula (II) 3+ complex

[0068] [ka] (II)

[0069] (Wherein, Ar is

[0070] [ka] and [ka] is a group selected from # is the connection to X, X is CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # is a group selected from * is the link to Ar, # is the linkage to the acetate residue, R 7 is a hydrogen atom or a group selected from an alkyl group having 1 to 3 carbon atoms, -CHOH, -(CH)OH, and -CHOCH; R 8 is a group selected from an alkoxy group having 2 to 4 carbon atoms, (H3C-CHO)-(CH2)2-O-, (H3C-CHO)-(CH2)2-O-(CH2)2-O- and (H3C-CHO)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 9 and R 10 are each independently a hydrogen atom, Or, it is a drug containing its stereoisomer, tautomer, hydrate, solvate or salt, or a mixture thereof.

[0071] The term "C1-C3 alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group having 1, 2, or 3 carbon atoms, e.g., methyl, ethyl, n-propyl, or isopropyl. The term "C2-C4 alkyl group" refers to a linear or branched saturated monovalent hydrocarbon group having 2, 3, or 4 carbon atoms.

[0072] The term "alkoxy group having 2 to 4 carbon atoms" denotes a linear or branched saturated monovalent group of the formula (C2-C4 alkyl)-O-, where the expression "C2-C4 alkyl" is as defined above, for example, a methoxy group, an ethoxy group, an n-propoxy group, or an isopropoxy group.

[0073] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium 2,2′,2″-(10-{1-carboxy-2-[2-(4-ethoxyphenyl)ethoxy]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (see, e.g., WO 2022 / 194777, Example 1).

[0074] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium 2,2′,2″-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate (see, e.g., WO 2022 / 194777, Example 2).

[0075] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium 2,2′,2″-{10-[(1R)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate (see, e.g., WO 2022 / 194777, Example 4).

[0076] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium (2S,2'S,2''S)-2,2',2''-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) (see, e.g., WO 2022 / 194777, Example 15).

[0077] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium 2,2′,2″-{10-[(1S)-4-(4-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate (see, e.g., WO 2022 / 194777, Example 31).

[0078] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium 2,2′,2″-{(2S)-10-(carboxymethyl)-2-[4-(2-ethoxyethoxy)benzyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate.

[0079] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium 2,2′,2″-[10-(carboxymethyl)-2-(4-ethoxybenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]triacetate.

[0080] In one embodiment of the present disclosure, the imaging agent is a drug comprising gadolinium(III) 5,8-bis(carboxylatomethyl)-2-[2-(methylamino)-2-oxoethyl]-10-oxo-2,5,8,11-tetraazadodecane-1-carboxylate hydrate (also known as gadodiamide).

[0081] In one embodiment of the present disclosure, the imaging agent is a drug comprising gadolinium(III) 2-[4-(2-hydroxypropyl)-7,10-bis(2-oxide-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]acetate (also known as gadoteridol).

[0082] In one embodiment of the present disclosure, the imaging agent is an agent comprising gadolinium(III) 2,2′,2″-(10-((2R,3S)-1,3,4-trihydroxybutan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate (also referred to as gadobutrol or Gd-DO3A-butrol).

[0083] In a first step, a first representation and a second representation are received or generated.

[0084] The term "receiving" encompasses both obtaining a representation and accepting a representation transmitted to, for example, a computer system of the present disclosure. The representation may be received from a computed tomography system, a magnetic resonance imaging system, or an ultrasound scanner. The radiological images may be read from one or more data memories and / or transmitted from another computer system.

[0085] The term "generate" preferably means that a representation is generated based on another (e.g., received) representation or based on a plurality of other (e.g., received) representations. For example, the received representation may be a representation of the inspection area of ​​the inspected object in real space. Based on this real space representation, it is possible to generate a representation of the inspection area of ​​the inspected object in frequency space, for example, by a transform operation (e.g., Fourier transform). Other ways of generating a representation based on one or more other representations are described herein.

[0086] The first and second representations represent the examination region in real space or frequency space.

[0087] The radiological images obtained as a result of a radiological examination are often obtained as a representation of real space (also called image space).

[0088] "Real space" refers to ordinary three-dimensional Euclidean space, which corresponds to the space that we humans experience and move through intuitively. Therefore, representations of real space are familiar to humans.

[0089] In a representation in real space, also referred to herein as a real space depiction or real space representation, the examination area is typically represented by a number of image elements (pixels or voxels), which may for example be in a raster array, where each image element represents a portion of the examination area and may be assigned a color or gray value. A format widely used in radiology for storing and processing real space representations is the DICOM format. DICOM (Digital Imaging and Communications in Medicine) is an open standard for storing and exchanging information in medical image data management.

[0090] "Frequency space" refers to the domain in which a signal is considered to be the sum of its individual frequency components.

[0091] In a representation in frequency space, also referred to herein as a frequency space representation or frequency space representation, the examination region is represented by a superposition of fundamental vibrations. For example, the examination region may be represented by a sum of sine and / or cosine functions with different amplitudes, frequencies, and phases. The amplitudes and phases may be plotted as a function of frequency, for example, in a two-dimensional or three-dimensional representation. Typically, the lowest frequency (the origin) is located at the center. The further away from this center, the higher the frequency. Each frequency can be assigned an amplitude that represents the frequency in the frequency space representation, and a phase that indicates the degree of deviation of the respective vibration relative to the sine or cosine wave.

[0092] Raw data (so-called k-space data) obtained in a magnetic resonance imaging study is an example of a representation in frequency space. Such raw data (k-space data) from a magnetic resonance imaging study can be directly used as the first and / or second representation in the context of the present disclosure.

[0093] A representation in real space can be transformed (converted) into a representation in frequency space, for example, by a Fourier transform operation, and conversely, a representation in frequency space can be transformed (converted) into a representation in real space, for example, by an inverse Fourier transform.

[0094] Details regarding real-space and frequency-space representations and the conversion between them are available in many publications, see for example https: / / see.stanford.edu / materials / lsoftaee261 / book-fall-07.pdf.

[0095] Before transforming the real-space representation into a frequency-space representation, it is possible to co-register the real-space representation. "Co-registration" (also known in the prior art as "image registration") is used to bring two or more real-space representations of the same examination area into the best possible match with each other. One of the real-space representations is defined as the reference image, and the other is called the target image. A compensatory transformation operation is calculated to best match the target image to the reference image.

[0096] Co-registration of representations in frequency space is also possible. Note that translations in real space constitute additive linear phase ramps in frequency space, while scaling and rotation are preserved by Fourier and inverse Fourier transforms. That is, scaling and rotation in frequency space are also scaling and rotation in real space. (See, e.g., S. Skare: Rigid Body Image Realignment in Image Space vs. k-Space, ISMRM SCIENTIFIC WORKSHOP on Motion Correction, 2014, https: / / cds.ismrm.org / protected / Motion_14 / Program / Syllabus / Skare.pdf).

[0097] It should be noted that the co-registration in frequency space does not need to be very accurate, since high frequencies that indicate image details and therefore co-registration inaccuracies are attenuated by the frequency filter, which is an advantage of the approach described in this disclosure compared to approaches that perform operations in real space.

[0098] A third representation is generated based on the first representation and the second representation.

[0099] The third representation represents the examination region in real or frequency space.

[0100] The third representation represents the signal enhancement (contrast agent signal representation) caused in the examination region by the second amount of contrast agent, in other words, the third representation includes the difference in the second representation compared to the first representation caused by the second amount of contrast agent.

[0101] In a preferred embodiment, generating the third representation comprises subtracting the first representation from the second representation, or in other words, in a preferred embodiment, the third representation is the difference between the first representation and the second representation.

[0102] The subtraction may be performed in real space or frequency space.

[0103] If the first and second representations represent the examination region in real space, the subtraction of the first representation from the second representation is preferably performed in real space, resulting in a third representation (contrast agent signal representation) in real space.

[0104] If the first and second representations represent the examination region in frequency space, the subtraction of the first representation from the second representation is preferably performed in frequency space, resulting in a third representation (contrast agent signal representation) in frequency space.

[0105] However, it is also possible to first transform the first representation in real space and the second representation in real space into a first representation in frequency space and a second representation in frequency space, and generate the third representation in frequency space by subtracting the first frequency space representation from the second frequency space representation.

[0106] Similarly, it is also possible to first convert the first representation in frequency space and the second representation in frequency space into the first representation in real space and the second representation in real space, and then generate the third representation in real space by subtracting the first real space representation from the second real space representation.

[0107] Preferably, generating the third representation in frequency space is based on the first representation in frequency space and the second representation in frequency space, wherein in such third frequency space representation each frequency is represented by an amplitude value, the more strongly a frequency is affected by the second amount of contrast agent, the higher this value.

[0108] FIG. 1 shows, by way of example, a schematic representation of an embodiment of the generation of a third representation based on a first representation and a second representation.

[0109] FIG. 1 shows various representations of the inspection area to be inspected.

[0110] First Representation R1 I represents the examination region in real space without contrast agent or after administration of a first amount of contrast agent. The examination region shown in FIG. 1 includes a pig liver. The first expression R1 I is a magnetic resonance image.

[0111] First real space representation R1 I is a first representation R1 of the examination region in frequency space by a transformation operation T, for example a Fourier transform. F The first frequency space representation R1 F is a first real space representation R1 without contrast agent or after administration of a first amount of contrast agent. I represents the same inspection area of ​​the same inspection object.

[0112] First frequency space representation R1 F is the inverse transformation operation T -1 The first real space representation R1 I The inverse transformation operation T -1 is the inverse transform of the transform operation T.

[0113] Second representation R2 I is the first expression R1 I The same inspection area of ​​the same inspection object is represented in real space by a second real space representation R2. I represents the examination region after administration of a second amount of contrast agent, which is greater than the first amount (which may be zero, as mentioned above). The second representation R1 I Similarly, magnetic resonance imaging is also used. The contrast agent used in the example shown in FIG. 1 is a hepatobiliary MRI contrast agent. Hepatobiliary contrast agents are characterized by being specifically taken up by liver cells (hepatocytes), accumulating in functional tissue (parenchymal tissue), and enhancing contrast in healthy liver tissue. An example of a hepatobiliary contrast agent is the disodium salt of gadoxetic acid (Gd-EOB-DTPA disodium), which is described in U.S. Pat. No. 6,039,931 and is commercially available under the trade names Primovist® and Eovist®. Further hepatobiliary contrast agents are described, inter alia, in WO 2022 / 194777.

[0114] Second real space representation R2 I In the second volume of contrast agent, contrast between the liver tissue and the surrounding tissue is enhanced.

[0115] Second real space representation R2 I is obtained by a transformation operation T into a second representation R2 of the test region in frequency space. F The second frequency space representation R2 F Similarly, after administration of a second amount of contrast agent, a second real space representation R2 I represents the same inspection area of ​​the same inspection object.

[0116] The second frequency space representation R2 F is the inverse transformation operation T -1 The second real space representation R2 I can be converted to

[0117] First frequency space representation R1 F and the second frequency space representation R2 F The third frequency space representation R3 is based onF In the example shown in FIG. 1, the third frequency space representation R3 F is the second frequency space representation R2 F and the first frequency space representation R1 F The difference between (R3 F =R2 F -R1 F ).

[0118] The third frequency space representation R3 F may be normalized, i.e., the amplitude values ​​may be multiplied by a factor such that the highest amplitude values ​​are represented by a hue of, for example, "white" and the lowest amplitude values ​​are represented by a hue of, for example, "black."

[0119] Such normalization may also involve setting to zero (or another value) any negative values ​​that may arise when subtracting the first representation from the second representation to avoid negative values.

[0120] The third frequency space representation R3 F represents the contrast enhancement produced in the examination region by the second amount of contrast agent.

[0121] In a further step, a weighted third representation can be generated based on the third representation. Such weighting of the third representation allows frequencies that contribute more to contrast to be weighted more heavily than frequencies that contribute less to contrast. The term "contrast" refers to a real-space representation that corresponds to a frequency-space representation. In the frequency-space representation, contrast information is represented by low frequencies, and information about fine structure is represented by high frequencies. Image noise is typically evenly distributed across the frequency representation. Therefore, a weighted third representation can be generated by applying a frequency-dependent weighting function to the third representation, in which low frequencies are weighted more heavily than high frequencies. The frequency-dependent weighting function has the effect of a filter. The filter improves the signal-to-noise ratio by reducing the spectral noise density at high frequencies.

[0122] The weighting of the third representation (i.e., generation of the weighted third representation) is performed in frequency space. If the third representation is a real-space representation, it can be transformed into a frequency-space third representation by a Fourier transform operation.

[0123] The weighting of the third representation in frequency space can be achieved by multiplying the third representation in frequency space by a frequency-dependent weighting function. In such a frequency-dependent weighting function, a weighting factor is assigned to each frequency. If the weighting factor for a particular frequency is, for example, zero, when the third representation in frequency space is multiplied by the frequency-dependent weighting function, the amplitude of the corresponding frequency in the third representation is set to zero, i.e., the frequency is removed. If the weighting factor for a particular frequency is, for example, one, when the third representation in frequency space is multiplied by the frequency-dependent weighting function, the amplitude of the corresponding frequency in the third representation remains unchanged, i.e., the frequency remains unchanged. If the weighting factor for a particular frequency is, for example, 0.5, when the third representation in frequency space is multiplied by the frequency-dependent weighting function, the amplitude of the corresponding frequency is reduced to half its value, i.e., the corresponding frequency is attenuated in the third representation in frequency space. If the weighting factor for a particular frequency is, for example, 2, then multiplying the third representation in frequency space by the frequency-dependent weighting function doubles the amplitude of the corresponding frequency, i.e., the corresponding frequency is enhanced in the third representation in frequency space.

[0124] In the frequency-dependent weighting of the third representation, the amplitude of low frequencies is preferably multiplied by a higher weighting factor than the amplitude of high frequencies, and in a preferred embodiment, the higher the frequency, the lower the weighting factor by which the amplitude of the frequency is multiplied.

[0125] An example of a frequency-dependent weighting function is shown in FIG.

[0126] Figure 2 shows an example of a weighted third representation R3 F,w FIG. 2 shows the generation of the third frequency space representation R3 already shown in FIG.F The third frequency space representation R3 F The amplitude values ​​of are multiplied by weighting factors. The weighting factors are frequency dependent, i.e., they are functions of frequency. For illustrative purposes, the weighting function WF is shown in two-dimensional form in Figure 2. The weighting function WF shows the weighting factors wf as a function of frequency f in one dimension (along the dash-dotted line). Within the same image plane, the weighting function also has the same shape in the direction perpendicular to the dash-dotted line. However, in this example, the representation R3 F is rectangular rather than square, so it is compressed in that direction.

[0127] The weighting function WF is the low frequency (in the example shown, the frequency is expressed as R3 F (increasing from the center to the outside) and the amplitude of the high frequency (which is expressed as R3 F (further away from the center of the signal) are multiplied by a higher weighting factor, i.e., lower frequencies are given a higher weight than higher frequencies. This is the weighted representation R3 F,w In the representation, the gray values ​​decrease towards the edge of the representation. F The overall brightness is darker than in the R3 case. F This can be seen from the fact that the decrease is more rapid from the center to the outside than in the case of

[0128] Weighted Representation R3 F,w can be normalized, i.e., the amplitude values ​​can be multiplied by a factor such that the highest amplitude values ​​are represented by a hue of, for example, "white" and the lowest amplitude values ​​are represented by a hue of, for example, "black."

[0129] Figure 3 shows an example of a frequency-dependent weighting function that can be used to weight the third representation. For simplicity, the weighting function is represented as a two-dimensional graph in which the weighting coefficient wf (vertical axis) is plotted as a function of frequency f (horizontal axis).

[0130] Figure 3(a) shows the weighting function WF already shown in Figure 2. In this weighting function, for example, the weighting coefficients may decrease exponentially from the center as the frequency increases.

[0131] FIG. 3(b) shows a weighting function in which the weighting coefficients decrease linearly from the center as the frequency increases.

[0132] FIG. 3(c) shows a weighting function in which the weighting coefficients decrease in an inverse parabolic fashion from the center as the frequency increases.

[0133] FIG. 3(d) shows a weighting function in which the weighting coefficients are constant within a defined range around the center, and then decrease exponentially from a threshold frequency.

[0134] FIG. 3(e) shows a weighting function in which the weighting coefficients have a cosine shape about the center.

[0135] FIG. 3(f) shows a weighting function in which the weighting coefficients have the shape of a step function about the center.

[0136] FIG. 3(g) shows a weighting function whose weighting coefficients have the shape of a Gaussian distribution function about the center.

[0137] Figure 3(h) shows a weighting function where the weighting coefficients have the shape of a Hann function about the center.

[0138] It is also possible to combine the illustrated weighting functions with other weighting functions. Examples of other weighting functions can be found, for example, at: https: / / de.wikipedia.org / wiki / Fensterfunktion#Beispiele_von_Fensterfunktionen; FJ Harris et al.: On the Use of Windows for Harmonic Analysis with the Discrete Fourier Transform, Proceedings of the IEEE, vol.66, No.1, 1978; https: / / docs.scipy.org / doc / scipy / reference / signal.windows.html; KMMPrabhu: Window Functions and Their Applications in Signal Processing, CRC Press, 2014, 978-1-4665-1583-3

[0139] The weighting functions that can be used are also referred to as window functions in this document.

[0140] For weighting k-space data in MRI image processing and spectroscopy, it is preferable to use weighting functions that have proven useful, such as Hann functions (also known as Hann windows; see, e.g., R. Pohmann et al.: Accurate phosphorus metabolite images of the human heart by 3D acquisition-weighted CSI, Magnetic Resonance in Medicine: An Official Journal of the International Society for Magnetic Resonance in Medicine 45.5 (2001): 817-826).

[0141] Another preferred weighting function is the Poisson function (Poisson window).

[0142] In a further step, a fourth representation is generated by combining the first representation with the optionally weighted third representation, such that the combination transfers information to the first representation regarding the contrast enhancement caused by the second amount of contrast agent in the examination region.

[0143] The combination may for example be or include the addition of a first representation with an optionally weighted third representation, however multiplicative or non-linear combinations are also possible.

[0144] The generation of the fourth representation based on the optionally weighted third representation can be performed in real space or frequency space, i.e., the optionally weighted third frequency space representation can be combined with the first frequency space representation (e.g., the optionally weighted third frequency space representation is added α times to the first frequency space representation), or the optionally weighted third real space representation can be combined with the first real space representation (e.g., the optionally weighted third real space representation is added α times to the first real space representation).

[0145] It is also possible in principle to generate a fourth representation (in real space or frequency space) by combining an optionally weighted third representation with the second representation (e.g., by adding the optionally weighted third representation α times to the second representation).

[0146] 4 shows, by way of example, a schematic representation of an embodiment of the generation of the fourth representation. In FIG. 4, a fourth representation R4 of the test area of ​​the test object in frequency space is F is the first frequency space representation R1 already shown in FIG. F and the weighted representation R3 already shown in Figure 2. F,w The fourth representation R4 is generated by combining the four expressions R1 and R2. In this example, the combination is done by addition. F It is also possible to normalize

[0147] If the fourth representation is a frequency space representation (as shown in the example of Figure 4), then in a further step the fourth frequency space representation is converted into a fourth real space representation by a transformation operation (e.g., an inverse Fourier transform). If the fourth representation is a real space representation (e.g., because it has been generated by combining the first real space representation and an optionally weighted third real space representation), then no such transformation operation to real space is necessary.

[0148] The fourth real-space representation of the examination region may be output (eg, displayed on a screen or printed using a printer), stored in a data memory, and / or transmitted to another computer system.

[0149] FIG. 5 shows an example of the inverse transform operation T -1 , the fourth representation R4 of the examination area in frequency space already shown in FIG. F from the fourth representation R4 of the inspection area in real space I It shows schematically how is generated.

[0150] FIG. 6 shows, by way of example, a schematic representation of the complete process already partially shown in FIGS.

[0151] If the third representation is generated by subtracting the first representation from the second representation, then adding the (unweighted) third representation to the first representation will again result in the second representation.

[0152] Adding a weighted third representation to the first representation results in a representation that is different from the second representation.

[0153] The weighting focuses on the contrast information, ie, features in the fourth representation are emphasized by the increased contrast caused by the second amount of contrast agent.

[0154] By adding an optionally weighted third representation to the first representation multiple times, further contrast enhancement can be achieved without amplifying interference and / or noise as much as the contrast enhancement.

[0155] Thus, the optionally weighted third representation can be multiplied by a gain factor α and added to the first representation. The gain factor α represents the degree of contrast increase in the fourth representation. An enhancement less than 1 can be selected, resulting in a lower contrast between areas with and without contrast agent in the fourth representation than in the second representation. Similarly, it is possible to achieve a contrast enhancement greater than that produced by a standard dose of contrast agent. In the method described in WO 2019 / 074938, such contrast enhancement is not possible unless people are administered a higher-than-standard dose of contrast agent, i.e., outside the range approved by regulatory authorities, to generate the training data.

[0156] The gain factor α may be user-selectable, i.e., variable, or may be predefined, i.e., predetermined.

[0157] 7 shows, by way of example, a schematic representation of different representations of the examination area of ​​an examination object in real space, which depend on the gain factor α, which in this example can take the values ​​0, 1, 2, 3, 4.

[0158] A gain factor of α=0 means that no contrast enhancement is performed in the first representation, and therefore this representation shows the original first representation in real space.

[0159] A gain factor of α=1 means that the optionally weighted third representation is added once to the first representation (in frequency or real space). The contrast enhancement is similar to that in the second representation, but with weighting (e.g., low frequency weighting) resulting in less noise and interference.

[0160] A gain factor of α=2, 3, or 4 means that an optionally weighted third representation (in frequency or real space) is added two, three, or four times to the first representation. The larger the gain factor, the more contrast is enhanced.

[0161] In the example shown in Figure 7, in all cases an integer multiple of the optionally weighted third representation is added to the first representation. Of course, it is also possible to add a non-integer multiple of the optionally weighted third representation to the first representation (e.g. α=1.5 or α=3.7 or α=4.159). This means that the enhancement can be continuously increased.

[0162] Negative α values ​​are also possible, for example, a negative α value can be selected so that parts of the examination region where signal enhancement by the contrast agent occurs in the representation generated by the measurement are completely dark (black) in the artificially generated representation.

[0163] Thus, the gain factor α is a positive or negative real number.

[0164] The gain factor α can also be determined in an automated manner. "Automated" means without human intervention. For example, at least one region in the real-space representation of the first and / or second representation can be defined and / or selected by a user, and the gain factor α can be set so that the gray value (or a different tone value, in the case of a representation other than a gray-value representation) in the real-space representation is a defined value and / or this gray value is above or below a threshold value and / or two gray values ​​in two different selected or defined regions are at a defined distance from each other and / or this distance is above or below a threshold value. Other criteria can also be used in the automatic determination of the gain factor α. The criterion for the automatic determination of the gain factor α can be, for example, based on histograms of the real-space representations of the first, second, third, weighted third, and / or fourth representations. Such histograms can indicate the number of image elements having a defined tone value or gray value.

[0165] 8 illustrates a preferred embodiment of the output of an artificial contrast radiological image of an examination region by a computer system / computer program to a user of the computer system and / or computer program of the present disclosure.

[0166] a first real space representation R1 of the inspection area of ​​the inspection object; I , a second real space representation R2 of the inspection area of ​​the inspection object I , and a fourth real space representation R4 of the inspection area of ​​the inspection object I is displayed to the user (e.g., on a monitor).

[0167] First Representation R1 I represents the examination region without contrast agent or after administration of a first amount of contrast agent.

[0168] Second representation R2 I represents the examination region after administration of a second amount of contrast agent, the second amount being greater than the first amount.

[0169] Fourth Representation R4 I represents the contrast-enhanced examination region. The contrast between the area without contrast and the area with contrast is given by the second expression R2 I The fourth expression R4 I In this case, it is large.

[0170] Fourth Representation R4 I was generated as described in this disclosure (see in particular the description of Figures 1-7).

[0171] All displayed representations are representations of the examination area in real space. In the example shown in Figure 8, the frequency space representation is not displayed to the user. This is also not usually expected, as many users are unfamiliar with frequency space representations.

[0172] Displayed representation R1 I , R2 I , R4 I Below this, a histogram of the representation is superimposed and displayed to the user.

[0173] Displayed representation R1 I , R2 I , R4 I Above the screen, three virtual sliders are provided for the user to adjust: The first slider, α, allows the user to freely select the gain factor α in the range of 1 to 10. This slider indicates that the gain factor can be increased continuously from 1 to 10.

[0174] The second slider β and the third slider γ allow the user to change the parameters of the weighting function, which can determine, for example, how sharply the weighting coefficient decreases with increasing frequency.

[0175] The output shown in Figure 8 shows the fourth representation R4 when the user makes a change with one of the sliders. IPreferably, the display of R4 is updated immediately. For example, the user may change the gain coefficient α, and the change in the gain coefficient α is reflected in the display R4. I This allows the user to instantly see how the fourth representation R4 of the inspection area is optimal for the user. I You can identify the settings that cause this.

[0176] Whenever any change is made to one of the parameters α, β and / or γ, the computer system generates a fourth representation R4 based on the changed parameters. I and display it in the background. The same is true for the fourth expression R4 I This also applies to histograms of

[0177] Contrast enhancement according to the present disclosure so far can result in undesirable contrast enhancement for the user. This is illustrated by an example, which is shown schematically in FIG.

[0178] FIG. 9 shows a first representation R1 of the inspection area of ​​the inspection object. I and the second representation R2 I The examination area includes the pig liver L and gallbladder B. The first representation R1 I represents the examination region in real space without contrast agent or after administration of a first amount of contrast agent. I represents the examination region in real space after administration of a second amount of contrast agent, which is greater than the first amount. The second representation R2 I , it can be seen that the gallbladder is partially filled with a fluid, for example, containing a contrast agent or other fluid, resulting in high contrast between the partially filled gallbladder and its surrounding areas.

[0179] The contrast enhancement described in this disclosure provides an artificial contrast radiological image R4 of the examination area. I In the image, the contrast between the partially filled gallbladder and the rest of the body is further enhanced. However, the user may be interested in contrast enhancement of the liver.

[0180] In a preferred embodiment, the computer system and computer program of the present disclosure are configured to receive input from a user. In the input, the user can designate one or more portions where contrast enhancement is not desired. The user can draw such portions in the first, second, and / or fourth representation in real space, for example, using a mouse or other input means. For example, in the example shown in FIG. 9, the user can designate one or more portions where contrast enhancement is not desired. I , the second representation R2 I and / or the fourth representation R4 I The gallbladder can be selected and / or highlighted in the image. The computer system and computer program may be configured to set the gray value or the tone value of all image elements (pixels, voxels) representing the (highlighted) gallbladder to zero, resulting in a representation R2 in which the gallbladder is represented by black image elements. I* As described in this disclosure, R1 I and R2 I* When contrast enhancement is performed based on the representation of (or based on the corresponding frequency space representation), the artificial contrast radiographic image R4 I* , which shows contrast enhancement, particularly between the liver L and other parts of the body, but the partially filled gallbladder is no longer depicted with enhanced contrast.

[0181] In a preferred embodiment, the portions that should not be contrast enhanced (should not be highlighted) are determined automatically. I and the second real space representation R2 I For every pair of corresponding image elements of (ie elements with the same coordinates), the quotient of the tone values ​​is determined.

number

[0182] where Q is the quotient of the grayscale values ​​and g2(x,y,z) is the second representation R2 Iis the gray level of the image element with coordinates x, y, z in the first representation R1 I is the gray level of the image element with the same coordinates x, y, z in the second representation. The gray level quotient Q is a measure of how brightly the image element with coordinates x, y, z is depicted in the second representation compared to the corresponding image element in the first representation. This indicates the degree of contrast enhancement caused by the second amount of contrast agent in the examination region represented by the image element with coordinates x, y, z.

[0183] The computer system and computer program may be configured to compare the quotient of the gray values ​​of all image elements with a predefined threshold, the predefined threshold defining the maximum contrast enhancement expected from the contrast agent.

[0184] If the quotient of the tone values ​​of the corresponding image elements is greater than a predefined threshold, the tone value of the corresponding image element can be set to zero.

[0185] FIG. 10 illustrates, by way of example, a schematic diagram of a computer system according to the present disclosure.

[0186] A "computer system" is an electronic data processing system that processes data according to programmable computational rules. Such a system typically consists of a "computer," a unit containing a processor that performs logical operations, and peripheral devices.

[0187] In computer technology, a "peripheral" refers to any device that is connected to a computer and used as a control and / or input / output device for the computer. Examples include monitors (screens), printers, scanners, mice, keyboards, drives, cameras, microphones, speakers, etc. Internal ports and expansion cards are also considered peripherals in computer technology.

[0188] The computer system (1) shown in FIG. 10 includes a receiving unit (10), a control and calculation unit (20), and an output unit (30).

[0189] The control and calculation unit (20) functions to control the computer system (1), coordinate the data flow between the various parts of the computer system (1), and perform calculations.

[0190] The control calculation unit (20) generating or causing a receiver (10) to receive a first representation in frequency or real space of an examination region of an examination subject without a contrast agent or after administration of a first amount of contrast agent; generating or causing a receiving unit (10) to receive a second representation in real space or frequency space of the examination region of the subject after administration of the second amount of contrast agent; generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation, the third representation representing the examination region in real space or frequency space; Optionally, generating a weighted third representation based on the third representation, comprising frequency-dependent weighting the third representation in frequency space; generating a fourth representation based on the optionally weighted third representation and the first or second representation, the fourth representation including adding the optional third representation multiplied by α to the first or second representation, where α is a positive or negative real number; If the fourth representation represents the test area in frequency space, converting the fourth representation to a representation of the test area in real space; The output unit (30) is configured to output the fourth representation of the examination region in real space and / or store it and / or transmit it to another computer system.

[0191] Figure 11 shows a schematic diagram of a further embodiment of a computer system, by way of example. The computer system 1 includes a processing unit 21 connected to a memory 22. The processing unit 21 and the memory 22 form a control and computing unit, as shown in Figure 10.

[0192] The processing unit (21) includes one or more processors, alone or in combination with one or more memories. The processing unit (21) may be conventional computer hardware capable of processing information such as digital images, computer programs, and / or other digital information. The processing unit (21) typically consists of an array of electronic circuits, some of which may be designed as integrated circuits or as multiple integrated circuits connected together (integrated circuits are sometimes referred to as "chips"). The processing unit (21) may be configured to execute a computer program, which may be stored in the processing unit's (21) working memory or in memory (22) of the same or a different computer system.

[0193] The memory 22 may be conventional computer hardware capable of temporarily and / or permanently storing information, such as digital images (e.g., representations of an examination area), data, computer programs, and / or other digital information. The memory 22 may include volatile and / or nonvolatile memory and may be non-removable or removable. Examples of suitable memory are RAM (random access memory), ROM (read-only memory), hard disk, flash memory, removable computer floppy disk, optical disk, magnetic tape, or combinations of the foregoing. Optical disks include read-only memory compact disks (CD-ROMs), read / write compact disks (CD-R / Ws), DVDs, Blu-ray disks, etc.

[0194] The processing unit (21) may be connected to the memory (22) as well as one or more interfaces (11, 12, 31, 32, 33) for displaying, transmitting, and / or receiving information. The interfaces may include one or more communication interfaces (11, 32, 33) and / or one or more user interfaces (12, 31). The one or more communication interfaces may be configured to transmit and / or receive information to and / or from, for example, an MRI scanner, a CT scanner, an ultrasound camera, another computer system, a network, a data memory, etc. The one or more communication interfaces may be configured to transmit and / or receive information via physical (wired) and / or wireless communication connections. The one or more communication interfaces may include one or more interfaces for connecting to a network using technologies such as cellular, Wi-Fi, satellite, cable, DSL, fiber optics, etc. In some embodiments, the one or more communication interfaces may include one or more short-range communication interfaces configured to connect devices via short-range communication technologies such as NFC, RFID, Bluetooth, Bluetooth LE, ZigBee, infrared (e.g., IrDA), etc.

[0195] The user interface may include a display (31). The display (31) may be configured to display information to a user. Suitable examples of displays include a liquid crystal display (LCD), a light-emitting diode display (LED), a plasma display panel (PDP), etc. The user input interfaces (11, 12) may be wired or wireless and may be configured to receive information from a user of the computer system (1), for example, for processing, storage, and / or display. Suitable examples of user input interfaces include a microphone, an image or video recording device (e.g., a camera), a keyboard or keypad, a joystick, a touch-sensitive surface (separate from a touchscreen or integrated with a touchscreen), etc. In some examples, the user interface may include automatic identification data capture (AIDC) technology for machine-readable information. This may include barcodes, radio frequency identification (RFID), magnetic strips, optical character recognition (OCR), integrated circuit cards (ICC), etc. The user interface may further include one or more interfaces for communicating with peripheral devices, such as a printer.

[0196] One or more computer programs (40) may be stored in memory (22) and executed by processor (21), thereby programming processor (21) to perform the functions described herein. The retrieval, loading, and execution of instructions in computer programs (40) may be performed sequentially, such that instructions are retrieved, loaded, and executed, respectively. However, retrieval, loading, and / or execution may also be performed in parallel.

[0197] The computer system of the present disclosure may be designed as a laptop, notebook, netbook and / or tablet PC, and may also be a component of an MRI scanner, a CT scanner or an ultrasound machine.

[0198] FIG. 12 illustrates, by way of example, a computer-implemented method embodiment generally in the form of a flowchart.

[0199] The method (100) is (110) receiving or generating a first representation in real space or frequency space of an examination region of an examination subject without a contrast agent or after administration of a first amount of a contrast agent; (120) receiving or generating a second representation in real space or frequency space of the examination region of the examination subject after administration of a second amount of contrast agent; (130) generating a third representation based on the first representation and the second representation, the third representation being generated by subtracting the first representation from the second representation; (140) Optionally, generating a weighted third representation including applying a frequency dependent weighting function to the third representation in frequency space; (150) Generating a fourth representation, including adding the optionally weighted third representation by α to the first representation or the second representation, where α is a positive or negative real number; (160) if the fourth representation represents the test area in frequency space, converting the fourth representation into a fourth representation of the test area in real space; (170) Outputting and / or storing the fourth representation of the inspection area in real space and / or transmitting the fourth representation of the inspection area in real space to another computer system.

[0200] The present invention can be used for a variety of purposes, and some examples of use are described below, but the present invention is not intended to be limited to these examples of use.

[0201] The first use case involves magnetic resonance imaging (MRI) for identifying intracerebral metastases and intracerebral tumors, such as malignant gliomas. Because these tumors grow in an infiltrative manner, accurately distinguishing between tumor and healthy tissue is difficult. However, determining the extent of the tumor is crucial for surgical resection. Distinguishing between tumor and healthy tissue can be facilitated by administering extracellular substances. With intravenous administration of the extracellular MRI contrast agent gadobutrol at a standard dose of 0.1 mmol per kg of body weight, intracerebral tumors are much easier to identify. At higher doses, the contrast between lesions and healthy brain tissue is further enhanced, and the detection rate of brain metastases increases linearly with the dose of the contrast agent (see, for example, M. Hartmann et al.: Does the administration of a high dose of a paramagnetic contrast medium (Gadovist) improve the diagnostic value of magnetic resonance tomography in glioblastomas? doi: 10.1055 / s-2007-1015623).

[0202] A single triple dose or a second booster is possible, up to a total dose of 0.3 mmol / kg body weight, at the expense of additional gadolinium exposure to the patient and surrounding area and additional costs for the second scan.

[0203] The present invention can be used to avoid exceeding the standard dose of contrast agent. A first MRI image can be generated without contrast agent or with a substandard dose, and a second MRI image can be generated with the standard dose. Based on these generated MRI images, a synthetic MRI image can be generated in which the contrast between the lesion and healthy tissue can be varied over a wide range by varying the gain coefficient α, as described in this disclosure. This allows for contrast that would otherwise be achieved only by administering a larger-than-standard dose of contrast agent.

[0204] Another use case involves reducing the amount of MRI contrast agent used in magnetic resonance imaging (MRI). Gadolinium-containing contrast agents, such as gadobutrol, are used in numerous examinations. They are used for contrast enhancement in skull, spine, and breast examinations. In the central nervous system, gadobutrol highlights areas of blood-brain barrier damage and / or vascular abnormalities. In breast tissue, gadobutrol visualizes the presence and severity of breast malignancies. Gadobutrol is also used in contrast-enhanced MRI angiography to diagnose stroke, detect tumor blood perfusion, and detect focal cerebral ischemia.

[0205] Due to concerns about increased environmental impact, costs to the healthcare system, and potential acute side effects and long-term health risks, especially with repeated and prolonged exposure, there is a desire to reduce the dosage of gadolinium-containing contrast agents, which can be achieved by the present invention.

[0206] A first MRI image can be generated without contrast and a second MRI image can be generated using a lower-than-standard dose of contrast. Based on these generated MRI images, a synthetic MRI image can be generated that allows for a wide range of contrast variations by varying the gain factor α as described herein. This allows for the same contrast to be achieved with a lower-than-standard dose of contrast agent.

[0207] Another example use relates to the detection, identification and / or characterization of liver lesions using hepatobiliary contrast agents such as Primovist®.

[0208] Primovist® is administered intravenously at a standard dose of 0.025 mmol / kg body weight. This standard dose is lower than the standard dose of 0.1 mmol / kg body weight for extracellular MRI contrast agents. Unlike contrast-enhanced MRI using extracellular gadolinium-containing contrast agents, Primovist® allows dynamic multiphase T1w imaging. However, due to the low dose of Primovist® and the transient motion artifact observed immediately after intravenous administration, radiologists recognize that contrast enhancement with Primovist® in the arterial phase is inferior to that with extracellular MRI contrast agents. However, for accurate lesion characterization, it is crucial to assess arterial phase contrast enhancement and the vascularity of focal liver lesions.

[0209] With the aid of the present invention it is possible to improve contrast, especially in the arterial phase, without the need to administer higher doses.

[0210] A first MRI image can be generated without contrast agent and a second MRI image can be generated in the arterial phase after administration of an amount of contrast agent equivalent to a standard dose. Based on these generated MRI images, a synthetic MRI image can be generated that allows for a wide range of arterial phase contrast to be varied by varying the gain factor α as described herein, thereby achieving contrast that would otherwise be achieved only by administering a larger than standard dose of contrast agent.

[0211] Another use case concerns the use of MRI contrast agents in computed tomography examinations.

[0212] In CT examinations, MRI contrast agents typically have a lower contrast-enhancing effect than CT contrast agents. However, there are cases where using MRI contrast agents in CT examinations can be advantageous. For example, when a surgeon performs minimally invasive surgery on a patient's liver, the surgeon monitors the procedure with a CT scanner. Compared to magnetic resonance imaging, computed tomography (CT) has the advantage of allowing more major surgical interventions in the examination area while generating CT images of the area being examined. However, only a limited number of surgical instruments and devices are compatible with MRI. Furthermore, the magnets used in MRI restrict access to the patient. Therefore, surgeons perform procedures in the examination area while visualizing the examination area with CT and following the procedure on a monitor.

[0213] For example, if a surgeon wishes to perform a procedure on a patient's liver, such as biopsying a liver lesion or removing a tumor, the contrast between the liver lesion or tumor and healthy liver tissue is not as pronounced in a CT image of the liver as it is in an MRI image after administration of a hepatobiliary contrast agent. Currently, no hepatobiliary contrast agents specific for CT are known and / or approved. The use of MRI contrast agents, particularly hepatobiliary MRI contrast agents, in computed tomography offers the possibility of distinguishing between healthy and diseased liver tissue and of performing surgery while simultaneously visualizing the liver.

[0214] The relatively low contrast enhancement achieved by MRI contrast agents can be improved with the aid of the present invention without the need to administer higher than standard doses.

[0215] A first CT image can be generated without the MRI contrast agent and a second CT image can be generated after administration of an amount of MRI contrast agent equivalent to a standard dose. Based on these generated CT images, by varying the gain factor α as described in this disclosure, a composite CT image can be generated in which the contrast produced by the MRI contrast agent can be varied over a wide range, thereby achieving contrast that would otherwise be achieved only by administering a larger than standard dose of MRI contrast agent.

Claims

1. A first representation (R1) of the examination area of ​​the subject in frequency space, either without contrast agent or after the application of a first amount of contrast agent. Ｆ ) receiving or generating A second representation (R2) in frequency space of the examination area of ​​the subject after the application of a second amount of contrast agent. Ｆ ) receiving or generating The first representation (R1 F) and the second representation (R2 Ｆ ) based on the third expression (R3 Ｆ The process involves generating a third representation (R3 F) in which the third representation represents the frequency-space signal enhancement caused by the second amount of contrast agent in the examination area. The third expression (R3 Ｆ By applying a frequency-dependent weighting function (WF) to ), a weighted third representation (R3) is obtained. Ｆ，ｗ To generate ) The first expression (R1 Ｆ By combining ) and the weighted third representation (R3 F, w), a fourth representation (R4 Ｆ To generate ) said fourth representation (R4 Ｆ ) into a representation of said examination region in real space (R4 Ｉ ), The representation of the inspection area in real space (R4 Ｉ Outputting and / or storing the representation of the inspection area in real space (R4 Ｉ ) to send to another computer system, Computer implementation methods, including those mentioned above.

2. The method according to claim 1, wherein the subject of the inspection is a living organism.

3. The method according to claim 1, wherein the subject of the examination is a mammal.

4. The method according to claim 1, wherein the subject of the examination is a human.

5. The method according to any one of claims 1 to 4, wherein the area being examined is the liver, kidney, heart, lungs, brain, stomach, bladder, prostate, intestines or a part thereof of the human body, or another part of the human body.

6. A first real-space representation (R1) that represents the examination area of ​​the subject to be examined in real space, either without contrast agent or after the application of the first amount of contrast agent. Ｉ ) receiving The first real-space representation (R1 Ｉ ) is the first representation (R1 Ｆ Converting to ) A second real-space representation (R2) of the examination area of ​​the subject to be examined after the application of the second amount of contrast agent. Ｉ ) receiving The second real-space representation (R2 Ｉ ) is the second representation (R2) of the inspection area of ​​the object being inspected in frequency space. Ｆ Converting to ) The method according to any one of claims 1 to 4, including the method described in any one of claims 1 to 4.

7. The method according to any one of claims 1 to 4, wherein generating the third representation (R3 F) based on the first representation (R1 F) and the second representation (R2 F) includes subtracting the first representation (R1 F) from the second representation (R2 F).

8. The method according to any one of claims 1 to 4, wherein combining the first representation (R1 F) and the weighted third representation (R3 F, w) includes adding the first representation (R1 F) and the weighted third representation (R3 F, w).

9. The method according to any one of claims 1 to 4, wherein the frequency-dependent weighting function (WF) is applied to the third expression (R3 F) to multiply the low-frequency amplitude values ​​by a weighting coefficient that is larger than that of the high-frequency amplitude values.

10. The method according to any one of claims 1 to 4, wherein when the frequency-dependent weighting function (WF) is applied to the third representation (R3F), the amplitude value is multiplied by a window function, and the window function is a Gaussian distribution function or a Hann function.

11. The method according to any one of claims 1 to 4, wherein combining the first representation (R1 F) and the weighted third representation (R3 F, w) includes multiplying the weighted third representation (R3 F, w) by α and adding it to the first representation (R1 F), where α is a positive or negative real number.

12. The method according to claim 11, further comprising receiving one or more values ​​of α from a user.

13. Real space representation of the first representation (R1 Ｉ ) or the real-space representation of the second representation (R2 Ｉ Receiving the first grayscale value of the first image element of ) Real space representation of the first representation (R1 Ｉ ) or the real-space representation of the second representation (R2 Ｉ ) receiving the second grayscale value of the second image element, The value of α is determined such that the difference between the first grayscale value and the second grayscale value is above or below a predetermined value or a predefined threshold. The method according to claim 11, further comprising:

14. Real space representation of the second representation (R2 Ｉ ) Receiving the specification of the area within To set the grayscale value of the aforementioned region to zero. From the real space representation, the second representation (R2 Ｆ To generate The method according to any one of claims 1 to 4, further comprising:

15. The first real-space representation of the first representation (R1 Ｉ Determine the first grayscale value for all coordinates of ). The second real space representation of the second representation (R2 Ｉ Determine the second grayscale value for all coordinates of ). The first real-space representation (R1 Ｉ ) and the second real-space representation (R2 Ｉ For all coordinates of ), determine the quotient between the second grayscale value and the first grayscale value. The second real-space representation (R2) where the quotient is greater than a predetermined threshold. Ｉ Set the gradation value of ) to zero. From the second real-space representation (R2I), the second representation (R2 Ｆ To generate ) The method according to any one of claims 1 to 4, further comprising:

16. Receiving unit (10), Control calculation unit (20), and A computer system (1) including an output unit (30), The control calculation unit (20) A first representation in frequency space of the examination area of ​​the subject being examined, either without contrast agent or after the application of a first amount of contrast agent (R1 Ｆ The receiving unit (10) receives the following: or the receiving unit (10) receives a first real-space representation (R1 I) that represents the examination area of ​​the examination target in real space, either without contrast agent or after the application of a first amount of contrast agent. When the receiving unit (10) receives the first real-space representation (R1 I), it converts the first real-space representation (R1 I) into the first representation (R1 F) of the inspection area of ​​the object to be inspected in frequency space. A second representation (R2) in frequency space of the examination area of ​​the subject after the application of a second amount of contrast agent. Ｆ The receiving unit (10) receives the following: or the receiving unit (10) receives a second real-space representation (R2 I) that represents the examination area of ​​the subject to be examined after the application of a second amount of contrast agent in real space. When the receiving unit (10) receives the second real-space representation (R2 I), it converts the second real-space representation (R2 I) into the second representation (R2 F) of the inspection area of ​​the object to be inspected in frequency space. The first representation (R1 F) and the second representation (R2 Ｆ ) based on the third expression (R3 Ｆ ) is generated, where the third representation (R3 F) represents the signal enhancement in frequency space caused by the second amount of contrast agent in the examination area, The third expression (R3 Ｆ By applying a frequency-dependent weighting function (WF) to ), a weighted third representation (R3) is obtained. Ｆ，ｗ ) generates, By combining the first representation (R1 F) and the weighted third representation (R3 F, w), a fourth representation (R4 Ｆ ) generates, The fourth expression (R4 Ｆ ) represents the inspection area in real space (R4 Ｉ Convert to ) and The output unit (30) outputs the representation (R4) of the inspection area in real space. Ｉ A computer system (1) configured to output, and / or store, and / or transmit to another computer system.

17. A computer program product including a data carrier in which a computer program (40) that can be loaded into the working memory (22) of a computer system (1) is stored, A first representation in frequency space of the examination area of ​​the subject being examined, either without contrast agent or after the application of a first amount of contrast agent (R1 Ｆ ) receiving or generating A second representation (R2) of the examination area of ​​the subject after application of the second amount of contrast agent in frequency space. Ｆ ) receiving or generating The first representation (R1 F) and the second representation (R2 Ｆ Based on ), the third expression (R3 Ｆ The means of generating the third representation (R3 F) is that the signal enhancement produced in the frequency space by the second amount of contrast agent in the examination area, By applying a frequency-dependent weighting function (WF) to the third representation (R3F, w), a weighted third representation (R3 Ｆ，ｗ To generate ) By combining the first representation (R1 F) and the weighted third representation (R3 F, w), a fourth representation (R4 Ｆ To generate ) The fourth expression (R4 Ｆ ) represents the inspection area in real space (R4 Ｉ Converting to ) The representation of the inspection area in real space (R4 Ｉ Outputting and / or storing the representation of the inspection area in real space (R4 Ｉ ) to send to another computer system, A computer program product that causes the computer system (1) to execute the process.

18. A kit comprising the computer program product and contrast agent described in Claim 17.

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