JP2023081490A - MRI imaging marker - Google Patents

Abstract

To provide a marker for MRI imaging which can be an indicator of a position in an MRI image.SOLUTION: A marker (1) for MRI imaging comprises: a non-magnetic container (2); and an MRI contrast medium contained in the container (2).SELECTED DRAWING: Figure 1

Description

Applied for application of Article 30, Paragraph 2 of the Patent Law ・Publication name: “The 75th Surgical Technique Study Group Program/Abstract Collection” Publication date: May 1, 2021 ・Research meeting name: The 75th Surgical Technique Study Group Place: Mishima Civic Cultural Center Date: May 14, 2021

The present invention relates to an MRI imaging marker for specifying the position of a lesion.

In recent years, advances in diagnostic technology have made it possible to detect minute lesions (small lesions) in the body and perform surgical treatment such as surgery. For example, methods have been developed to localize small lesions using imaging modalities such as Computed Tomography (CT) or Magnetic Resonance Imaging (MRI). Non-Patent Document 1 discloses a method of placing a microcoil in the vicinity of a lesion under CT guidance before surgery and excising the lesion based on the position of the microcoil.

Mayo et al. Lung nodules: CT-guided placement of microcoils to direct video-assisted thoracoscopic surgical resection. Radiology. 2009;250:576-585.

CT and MRI can detect small lesions that are difficult to detect with ultrasonography. However, these methods are difficult for real-time diagnostic imaging such as ultrasound diagnostic methods. Therefore, it is necessary to perform surgery after accurately ascertaining the position of small lesions by image diagnosis. It's easy to do.

The method described in Non-Patent Document 1 can be applied to CT, but not to MRI, which can detect small lesions that are difficult to detect with CT. This is because metal materials such as microcoils cannot be detected by MRI, and since MRI generates a strong magnetic field, there are many limitations in the procedure, such as the inability to use metal equipment.

It is an object of one aspect of the present invention to provide an MRI imaging marker that can serve as an index of a position in an MRI image.

In order to solve the above problems, an MRI imaging marker according to one aspect of the present invention includes a non-magnetic container and an MRI contrast agent contained in the container.

An MRI imaging marker according to one aspect of the present invention has a contrast region containing the MRI contrast agent and a non-contrast region not containing the MRI contrast agent, wherein at least two of the contrast regions are combined with at least one of the They may be formed at positions sandwiching the non-contrast region.

In the MRI imaging marker according to one aspect of the present invention, the contrast region is formed by arranging two or more cylindrical portions of the container containing the MRI contrast agent, and the non-contrast region is formed by: It may be a region sandwiched between at least two of the tubular portions.

In the MRI imaging marker according to one aspect of the present invention, the contrast region may be formed by arranging the cylindrical portions in a grid pattern.

In the MRI imaging marker according to one aspect of the present invention, the container may be made of flexible resin.

According to one aspect of the present invention, it is possible to realize an MRI imaging marker that can be used as an index of a position in an MRI image.

FIG. 3 illustrates a marker according to one embodiment of the invention; FIG. 4 is a diagram showing MRI images captured by changing the concentration of an MRI contrast medium; It is a figure which shows the result of FIG. 2 with a line graph. It is a figure which shows the state which installed the marker shown in FIG. 1 on the liver surface. FIG. 2 is an MRI image of the liver on which the markers shown in FIG. 1 are placed, showing horizontal and coronal sections; MRI images of the liver after excision of small lesions showing horizontal and coronal sections.

An embodiment of the invention will be described below, but the invention is not limited thereto. The present invention is not limited to each configuration described below, and various modifications are possible within the scope of the claims. In addition, the technical scope of the present invention also includes embodiments and examples obtained by appropriately combining technical means disclosed in different embodiments and examples. In addition, all the scientific literatures and patent documents described in this specification are used as references in this specification.

[1. Overview of the present invention]
One embodiment of the present invention provides an MRI imaging marker or the like that serves as an index for specifying the position of a lesion in an MRI image. In addition, "MRI image" indicates an image obtained by imaging by MRI.

Conventionally, in procedures such as surgery targeting small lesions in the body, in order to grasp the position of the target, (1) anatomical indices are relied upon, and (2) ultrasound enables real-time image diagnosis. Methods such as using diagnostic methods have been used. For example, in liver tumors, diagnostic ultrasound contrast agents have been developed, and their usefulness has made the use of diagnostic ultrasound during surgery more and more important.

On the other hand, with the recent remarkable development of diagnostic imaging techniques, there is an increasing number of cases where small lesions that can be detected only by highly sensitive imaging diagnostic methods such as CT or MRI should be targeted for treatment. For example, the detection sensitivity for small tumors of the liver is very high in MRI, and is said to exceed the power of diagnostic ultrasound.

A definitive solution to the problem of how to identify the position of such a small lesion during surgery and perform treatment including resection has not yet been found. It is clear that early detection of lesions by image diagnosis and early treatment are desirable. be.

Unlike ultrasonic diagnostic methods, when performing treatment such as surgery on lesions detected by CT or MRI, which are difficult to diagnose in real time, it is necessary for the operator to accurately grasp the position of the lesion. For example, for lesions of organs whose position relative to the skeleton is difficult to change, such as brain tumors or spinal cord tumors, the positional relationship between the skeleton and the lesion in images obtained by preoperative CT or MRI imaging is relied upon. , an intraoperative navigation system can be used to locate the lesion.

However, in the case of organs such as the lung or liver, where the position relative to the skeleton is likely to change, it is difficult to maintain the relative position of the organ relative to the skeleton between preoperative evaluation and lesion resection. difficult to use. In addition, when CT is used, there is a method using a microcoil or the like as a position marker, as shown in Non-Patent Document 1. No means can be used.

Small lesions such as early stage liver tumors that are difficult to detect without MRI can be identified by marking preoperatively or intraoperatively, and if small lesions can be accurately resected, lesions can be detected. lead to early detection and early treatment of In addition, it is expected that it can lead to improvement of patient's cancer treatment results. Accordingly, an embodiment of the present invention can also contribute to the achievement of Sustainable Development Goals (SDGs) such as Goal 3 "Good Health and Well-Being for All".

The present inventors are based on a new idea that has not existed in the past, that an MRI imaging agent, which has conventionally been used by administration to the living body, is used as a marker for MRI imaging in a manner different from administration to the living body. As a result, the inventors completed the present invention after intensive studies. An embodiment of the present invention will be described below.

As used herein, the term "living body" may be a human body, a non-human mammalian body, or a non-mammal animal body.

[2. marker〕
As shown in FIG. 1, a marker 1 (MRI imaging marker) according to one embodiment of the present invention includes a non-magnetic container and an MRI imaging agent contained in the container. In this embodiment, the container provided with the marker 1 is composed of a plurality of tubes 2 (cylindrical portions), and an MRI imaging agent is enclosed in the cavity of each tube 2 .

In this embodiment, the tubes 2 are Nelaton catheters made of polyvinyl chloride, each tube 2 having a length of approximately 10 cm and an outer diameter of 10 Fr (approximately 3.3 mm). In the marker 1, twelve such tubes 2 are arranged in a grid. The tubes 2 are 6 in the vertical direction and 6 in the horizontal direction toward the paper surface of FIG. ing.

Each tube 2 is supported by a support 3 formed of a sheet made of synthetic resin, which is a non-magnetic material, and their positional relationship is fixed. The support 3 is a substantially square sheet having lengths of about 11 cm in the vertical direction and the horizontal direction when viewed from the paper surface of FIG.

Since the marker 1 is provided with such a support 3, it becomes easy to arrange the plurality of tubes 2 so as to form a complicated shape such as a lattice. In addition, since the strength of the marker 1 is improved and handling becomes easy, it becomes easy to install and remove the MRI imaging object such as an organ. Note that the support 3 is not essential in the marker 1 .

The marker 1 has a contrast region 10 containing MRI imaging agent and a further non-contrast region 11 containing no MRI imaging agent. Specifically, in the marker 1 , the area where the tube 2 containing the MRI contrast agent is arranged is the contrast area 10 , and the other area is the non-contrast area 11 . In an MRI image obtained by MRI imaging the marker 1, a contrast region 10 is a region in which a signal is detected (enhanced), and a non-contrast region 11 is a region in which no signal is detected (non-enhanced).

The marker 1 is formed by arranging a plurality of tubes 2 in a lattice. Therefore, the contrast area 10 of the marker 1 is also formed as a grid area. Thus, the shape of the contrast region 10 becomes similar to the shape of the container containing the MRI contrast agent.

Note that the MRI contrast medium does not have to completely fill the lumen of the tube 2 . When an MRI contrast agent is enclosed in part of the tube 2 , the contrast region 10 is the region of the tube 2 containing the MRI contrast agent, and the other portion of the tube 2 is the non-contrast region 11 .

In the marker 1 , a non-imaging area 11 is formed by being sandwiched between at least two tubes 2 . In other words, in the marker 1 , at least two contrast regions 10 are formed at positions sandwiching at least one non-contrast region 11 . An example of the non-imaging region 11 in the marker 1 is a region surrounded by two vertically extending tubes 2a and 2b and two horizontally extending tubes 2c and 2d in FIG. The non-contrast region 11 can be said to be a region sandwiched by the contrast region 10 formed by the two tubes 2a and 2b and a region sandwiched by the contrast region 10 formed by the two tubes 2c and 2d.

In the marker 1, the non-imaging area 11 is formed as a total of 25 areas of 5 rows and 5 columns partitioned by the tubes 2 arranged in a lattice. The non-imaging area 11 is also a part of the support 3 and outside the outermost tube 2 in the vertical direction and the horizontal direction in plan view. Thus, at least part of the non-contrast region 11 of the marker 1 may be a region not sandwiched between the contrast regions 10 .

The MRI contrast agent included in the marker 1 is not particularly limited as long as it is a substance from which a signal is detected (enhanced) in an MRI image. For example, it is preferably a substance from which the signal is detected stronger than water. Marker 1 includes, but is not limited to, meglumine gadoterate (Magnescope®) as an MRI contrast agent. MRI contrast agents include, for example, gadolinium preparations such as sodium gadoxetate (Primovist; registered trademark), ferric ammonium citrate (Felicelts; registered trademark) and manganese chloride tetrahydrate (Bosedel; registered trademark), intravenous injection Alternatively, an MRI contrast agent approved for oral administration to a living body can be used.

In addition, since the marker 1 includes an MRI contrast agent enclosed in the tube 2, the MRI contrast agent itself does not usually come into contact with and affect the living body. Therefore, even a substance that has not been approved for administration to a living body can be applied as an MRI contrast agent provided in the marker 1 . However, considering the risk of damage to the tube 2 by surgical instruments, etc., it is preferable that the MRI contrast agent included in the marker 1 is an MRI contrast agent that is approved for administration to the living body and whose safety has been confirmed. .

The MRI contrast agent included in the marker 1 is not administered to a living body as in the conventional method, but is placed in a tube 2 and placed on an MRI imaging target to perform MRI imaging. Therefore, when using an MRI contrast agent approved for administration to a living body, it may be preferable that the concentration of the MRI contrast agent provided in the marker 1 is different from that when administered to the living body.

The concentration of the MRI contrast agent is preferably 1/10 or less, more preferably 1/20 or less, more preferably 1/40 or less of the concentration when administered to the living body, and 1 /100 or less is particularly preferable. In addition, the concentration of the MRI contrast agent is preferably 1/10000 or more, more preferably 1/1000 or more, and more preferably 1/500 or more of the concentration when administered to the living body. , 1/200 or more. With such density, the contrast region 10 of the marker 1 can be confirmed in the MRI image.

When adjusting the concentration by diluting the MRI contrast agent, the diluent is not particularly limited as long as it is a non-magnetic liquid whose signal intensity in the MRI image is lower than that of the MRI contrast agent included in the marker 1 . Considering the risk of tube 2 being damaged by a surgical instrument or the like, the diluent of the MRI contrast agent is preferably a liquid that can be administered to the living body. Such liquids include, for example, water, alcohols, organic solvents, and mixed solutions thereof, and these liquids may contain salts such as sodium chloride. Physiological saline is preferred as the diluent from the standpoint of availability and safety.

As described above, according to the marker 1 provided with the MRI imaging agent, by comparing the position of the marker 1 and the position of the lesion specified by the MRI image, compared to the case where the position of the skeleton or the like is used as an index, Accurate location of lesions can be identified. For example, under surgery, if an MRI image is captured by placing a marker 1 on an organ such as the liver before treatment, even if the position of the organ moves afterward, the positional relationship between the marker 1 and the organ is unlikely to change. . Therefore, the position of the lesion can be specified using the marker 1 as an index, and treatment such as surgery can be easily performed on the lesion. For small lesions, accurate localization is particularly important, so the usefulness of such a marker 1 is further enhanced.

Further, the marker 1 is formed with a grid-like contrast region 10 formed by a plurality of tubes 2 and a non-contrast region 11 sandwiched between these tubes 2 . Therefore, if the marker 1 is placed so as to cover the range in which the lesion is thought to exist in the organ or the like to be imaged by MRI, it can be easily determined which position in the lattice-shaped contrast region 10 the lesion exists near. recognizable. Therefore, by using the marker 1, the position of a lesion in an organ or the like to be imaged by MRI can be specified very accurately.

Also, the tube 2 is made of polyvinyl chloride and has flexibility. Therefore, the marker 1 can flexibly bend according to the surface shape of an organ or the like, and can have a three-dimensional shape that satisfactorily follows the surface of the organ or the like.

In MRI imaging, a plurality of tomographic MRI images, such as horizontal, coronal, and sagittal slices, are typically obtained from different directions relative to the longitudinal axis of the body. If the marker 1 has a three-dimensional shape, the contrast region 10 can be easily detected in an MRI image taken from any direction. Therefore, according to the marker 1, it is easy to accurately specify the position of a lesion not only in a plane but also in a three-dimensional imaging target such as an organ.

Note that the horizontal section in MRI imaging indicates a section in which the top and bottom of the MRI image correspond to the ventral-back direction of the living body, and the left and right correspond to the lateral direction of the living body. A coronal section indicates a section in which the upper and lower sides of the MRI image correspond to the craniocaudal direction of the living body, and the left and right sides correspond to the lateral direction of the living body. In addition, the sagittal section indicates a section in which the upper and lower sides of the MRI image correspond to the cranio-caudal direction of the living body, and the left and right sides correspond to the ventral-dorsal direction.

(Modification)
The configuration of the marker 1 is not limited to the above, and various modifications are possible. For example, in the marker 1, the plurality of tubes 2 may not be arranged in a lattice pattern, but may be arranged in a so-called fence-like arrangement in which they are aligned in only one direction. Also, the intervals between the tubes 2 need not be constant.

Also, the container provided with the marker 1 may have a shape in which a single tube 2 is bent instead of a plurality of tubes 2 . In this case, the single tube 2 can be considered to be divided into a plurality of cylindrical portions with arbitrary positions such as bent portions or curved portions as boundaries. For example, in the single tube 2 , a non-imaging region 11 can be defined as a region sandwiched between two opposing cylindrical portions (two contrasting regions 10 ) separated by a bent portion.

Also, the container provided with the marker 1 may have a cylindrical portion like the tube 2 only partially, or may not have a cylindrical portion. As a form of a container that does not have a cylindrical portion, for example, a shape in which a plurality of small spherical (dot-shaped) containers are arranged regularly or irregularly on the sheet-like support 3 can be considered. In this case, it can be said that the marker 1 is formed with a plurality of dot-shaped contrast regions 10 and a non-contrast region 11 sandwiched between these contrast regions 10 .

When the marker 1 has a container having such a shape, it is possible to determine in the MRI image which contrast region 10 of the plurality of dot-shaped contrast regions 10 formed on the marker 1 has a lesion. Easy to identify.

The material of the container provided with the marker 1 is not particularly limited as long as it is a non-magnetic material, but it is preferably made of resin, and more preferably made of synthetic resin. Synthetic resins include, for example, polyvinyl chloride, polyethylene, polypropylene, polyethylene terephthalate, polyamide and polystyrene. Biomass-derived polymeric materials such as polylactic acid are also cited as examples of synthetic resins. “Made of synthetic resin” means that the main material of the container is such a synthetic resin, and may partially contain a material other than the synthetic resin. Moreover, if the container provided with the marker 1 is made of a non-magnetic material other than synthetic resin, it may be made of a non-magnetic metal material such as titanium.

If the container provided with the marker 1 is made of such a material, it is less likely to be affected by the magnetic field generated by MRI.

The material of the container provided with the marker 1 is preferably flexible, but is not limited to this. For example, the container included in the marker 1 may be formed in a three-dimensional shape instead of a planar shape, although it does not have flexibility. That is, the marker 1 may have a container having a three-dimensional shape that matches the shape of the MRI imaging target. According to such a configuration, even if the container provided with the marker 1 does not have flexibility, the marker 1 can be satisfactorily installed so as to follow the surface shape of the MRI imaging target.

The material of the support 3 included in the marker 1 may be a non-magnetic material like the container included in the marker 1, and is preferably made of synthetic resin. Further, the support 3 does not need to be sheet-like, and may be, for example, a tape-like or thread-like member for fixing the plurality of tubes 2 together.

[3. How to use the marker]
A method for diagnosing a lesion using Marker 1 and a method for operating a lesion using Marker 1 are also included in the scope of the present invention.

Specifically, the method for diagnosing a lesion according to one embodiment of the present invention is a method of diagnosing a lesion that can include an MRI imaging marker comprising a non-magnetic container and an MRI contrast agent contained in the container. A step of installing on a subject, a step of acquiring an MRI image of the MRI imaging target on which the MRI imaging marker is installed, and based on the position of the MRI imaging marker and the position of the lesion from the MRI image, locating the lesion in the imaging subject.

Further, in a lesion surgery method according to an embodiment of the present invention, an MRI imaging marker comprising a non-magnetic container and an MRI contrast agent contained in the container is placed on an MRI imaging target that may include a lesion. obtaining an MRI image of the MRI imaging target on which the MRI imaging marker is placed; and the imaging specified based on the position of the MRI imaging marker and the position of the lesion in the MRI image. and marking the location of the lesion in the subject.

The MRI imaging marker (marker 1) and the method of identifying the lesion position based on the position of the MRI imaging marker and the position of the lesion are described in [2. marker] can be incorporated as appropriate. Moreover, a conventionally known method can be used as a method of acquiring an MRI image.

An MRI imaging target is not particularly limited, but includes, for example, an organ in a living body. In particular, an organ whose position relative to the skeleton is likely to fluctuate is suitable for the diagnostic method or surgical method using Marker 1. This is because the positional relationship between the skeleton and the organ of such an organ is likely to change, and it is difficult to specify the position of the lesion based on the MRI image after the MRI imaging. Organs with a variable position relative to the skeleton include, for example, organs in the thoracic or abdominal cavity, such as the heart, lungs, stomach, duodenum, liver, pancreas, kidneys, gallbladder, spleen, small intestine, large intestine, uterus, and prostate. .

The method of setting the marker 1 on the MRI imaging target is not particularly limited, but for example, it is sufficient to simply place the marker 1 on the MRI imaging target, using a fixture such as a non-magnetic needle or thread, the MRI imaging target. You may fix the marker 1 simply to. The fixture may be provided with the marker 1 or may be independent of the marker 1 .

A method for marking the position of a lesion in an MRI imaging target is not particularly limited, but for example, a method of burning the lesion or its surroundings with an electric scalpel or the like can be used.

An embodiment of the invention is described below.

[A. Examination of concentration of MRI contrast agent]
The optimum concentration of MRI contrast agent to be encapsulated in Marker 1 was investigated. As an MRI contrast medium, a 38% aqueous solution of meglumine gadoterate (Magnescope intravenous injection 38% syringe, Guerbet Japan Co., Ltd.) was used as a stock solution. FIG. 2 shows a bright-field image and an MRI image of a sample obtained by serially diluting an MRI contrast agent with physiological saline side by side. MRI imaging was performed using an intraoperative MRI apparatus (Fujifilm Healthcare Systems Co., Ltd., LUCENT-J). The magnetic field intensity in the intraoperative MRI apparatus was set to 0.4 T (Tesla).

As shown in FIG. 2, the samples used were sample A, which is a physiological saline solution (without an MRI contrast agent), and samples B to G, in which the MRI contrast agent is serially diluted with a physiological saline solution. The dilution ratio (concentration ratio to the stock solution) of the MRI contrast agent in samples B to G is B: 5 times (1/5), C: 10 times (1/10), D: 20 times (1/20), E: 40 times (1/40), F: 100 times (1/100), G: 200 times (1/200).

FIG. 3 shows the signal intensity of each sample in the obtained MRI image by a line graph. Quantification of the signal intensity in the MRI image was performed by creating a T1 relaxation curve using the inversion recovery method and determining the T1 value.

As shown in FIG. 3, the signal intensity was the strongest when the dilution ratio of the MRI contrast agent was 100 times (the concentration was 1/100 of the original solution). Further, the MRI image in FIG. 2 indicated that the signal intensity was stronger than that of the physiological saline when the MRI contrast agent was diluted 20 times or more (concentration was 1/20 or less of the original solution). In all of the surgical examples using Marker 1 shown below, the MRI contrast agent prepared at the highest signal intensity dilution concentration (dilution rate of 100 times, 1/100 of the original solution) was encapsulated in Marker 1 and performed.

[B. Example of surgery using markers]
Hepatocellular carcinoma was resected under MRI using Marker 1 shown in FIG. This surgery was performed as an epidemiological study on MRI-guided hepatectomy based on the content approved by the Hiroshima University Epidemiological Research Ethics Review Committee (permission number: E-1600, permission date: May 2019 10th of the month).

FIG. 4 is a diagram showing a state in which the marker 1 is placed in the liver L in one case of resection surgery for hepatocellular carcinoma using the marker 1. FIG. Specifically, after laparotomy under general anesthesia, a marker 1 was placed on the surface of the liver L so as to cover an approximate range where hepatocellular carcinoma was present, and MRI imaging was performed.

FIG. 5 is a diagram showing MRI images of horizontal and coronal sections obtained by MRI imaging. In FIG. 5 , the lesion of hepatocellular carcinoma is indicated by an arrow, and the position where the marker 1 is imaged is indicated by an arrowhead. As described above, since the marker 1 has a plurality of contrast regions 10 with non-contrast regions 11 interposed therebetween, the position of the marker 1 can be easily confirmed even in an MRI image showing a cross section of a three-dimensional organ.

The operator identified the position of the lesion by comparing the position of the marker 1 and the position of the lesion using the MRI image, and marked the lesion with an electric scalpel. Thereafter, the marker 1 was removed from the surface of the liver L, and excision was performed with an excision margin of approximately 2 cm around the lesion.

FIG. 6 is a diagram showing MRI images of horizontal and coronal sections obtained by performing MRI imaging again after excision. In FIG. 6, the arrow indicates the position where the lesion of hepatocellular carcinoma in the liver L was present. As shown in FIG. 6, it was confirmed that hepatocellular carcinoma was completely removed by appropriately excising a portion of the liver L centering on the lesion. Thus, after confirming the completion of resection by MRI images, the abdomen was closed to complete the operation.

Table 1 below shows the results of 12 cases of hepatocellular carcinoma resection performed under MRI using Marker 1. Table 2 below shows the results of 3 resections of hepatocellular carcinoma or metastatic liver tumor under MRI performed before the invention of Marker 1 and without using Marker 1. These surgeries were performed from July 2019 to October 2021.

The use of Marker 1 has the advantage that the operator can reliably identify and resect the lesion, but there was no noticeable increase in the operation time or blood loss compared to the conventional method. . That is, according to Marker 1, there is no major disadvantage in surgery compared to the conventional method, and good surgical results can be obtained even in cases with a high degree of difficulty in identifying the location of the lesion. was done.

The present invention can be used, for example, for MRI imaging under surgery.

1 Marker (marker for MRI imaging)
2 tube (container, cylindrical part)
3 support 10 imaging region 11 non-imaging region L liver

Claims (5)

An MRI imaging marker comprising a non-magnetic container and an MRI contrast agent contained in the container. Having a contrast region containing the MRI contrast agent and a non-contrast region not containing the MRI contrast agent,
2. The MRI imaging marker according to claim 1, wherein at least two of said contrast regions are formed at positions sandwiching at least one of said non-contrast regions. The contrast region is formed by arranging two or more cylindrical portions of the container that enclose the MRI contrast agent,
3. The MRI imaging marker according to claim 2, wherein said non-imaging region is a region sandwiched between said at least two cylindrical portions. 4. The MRI imaging marker according to claim 3, wherein the imaging region is formed by arranging the tubular portions in a grid pattern. The MRI imaging marker according to any one of claims 1 to 4, wherein the container is made of flexible resin.

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