Patent Application
20220354615
The present invention relates to a medical image guidance marker.
Cancer therapy performed under the guidance of an imaging modality such as magnetic resonance imaging (MRI), ultrasound, or CT is now in widespread use. Even in the case where cancer cannot be identified merely depending on the depictability of the cancer in an organ on images themselves, another technology is also available that allows recording of locations subjected to needle biopsy or the like as spatial coordinates. When the location of the cancer lesion is identified with reference to images or the presence of cancer is found through needle biopsy, the three-dimensional positional information of the cancer lesion can be grasped easily by placing, in a spatial location where the cancer lesion is present, an implantable marker that can be visualized using various types of imaging modalities. In particular, MRI and ultrasound are imaging technologies that do not at all involve radiation exposure, unlike CT. Accordingly, they can be used repeatedly for a long period of time and thus are of great utility to provide image guidance. In addition, MRI and ultrasound imaging technologies have made dramatic advances, and for example, concerning prostate cancer imaging technologies, MRI and ultrasound offer features that CT does not have. There have been many reports that fusion of MRI and ultrasound contributes to the improvement in diagnostic accuracy. There are quite a few situations where it is clinically necessary to use them in combination, more specifically, to use them respectively or in combination for different purposes like diagnosis and guidance while utilizing the advantages of the respective technologies. However, MRI and ultrasound are disadvantageous in that, when an implantable marker is used in imaging, artifacts are liable to occur owing to the presence of the marker, resulting in degraded imaging accuracy. An artifact refers to a phenomenon in which, in a magnetic field environment of MRI and the like, image distortion is caused owing to the difference in magnetic susceptibility between a metal object and a biological tissue around the metal object in the magnetic field. In ultrasonography, an artifact refers to an acoustic shadow and the like. Depending on the degree of the occurrence of artifacts, accurate surgery or accurate diagnosis may be hindered by the artifacts.
The material of the above-described implantable marker needs to have properties required for materials for medical use, such as biocompatibility, corrosion resistance, and workability. Examples of metal materials that meet the above requirements and have been in practical use include stainless steel, Co—Cr alloys, and Pt—W alloys (see Patent Document 1, for example). However, the above-described medical materials that have actually been in practical use are not able to suppress the occurrence of artifacts, because these medical materials have magnetic susceptibilities that differ greatly from those of biological tissues. On this account, as alloys aiming at artifact-free imaging, alloys of Au and Pd and alloys of Au and Pt have been proposed (see Patent Documents 2 to 4, for example). However, although these alloys exhibit a certain degree of effect on the occurrence of artifacts in a magnetic field environment, they cannot sufficiently suppress the occurrence of artifacts in ultrasonography and the like.
Patent Document 1: JP 2010-536491A
Patent Document 2: Japanese Patent No. 4523179
Patent Document 3: Japanese Patent No. 5550027
Patent Document 4: Japanese Patent No. 5582484
In light of the foregoing, it is an object of the present invention to provide a medical image guidance marker to be placed in a body, adapted to be applicable to at least all three types of imaging modalities, namely, MRI, ultrasound, and CT, and to minimize the occurrence of artifacts.
In order to achieve the above object, the present invention provides a medical image guidance marker to be placed in a body, wherein the medical image guidance marker is made of an alloy with a magnetic susceptibility in the range from −13 ppm to −5 ppm and has a shape of a coil, the coil is formed of a wire with a wire diameter of not less than 0.15 mm and not more than 0.45 mm and has a coil diameter of not less than 0.55 mm and not more than 1.20 mm, and the pitch of the coil is not less than 0.3 mm and not more than 1.5 mm and is not less than 1.8 times and not more than 4 times the wire diameter.
The medical image guidance marker according to the present invention is preferably such that the coil has a coil length of not less than 6 mm and not more than 7 mm.
The medical image guidance marker according to the present invention is preferably such that the alloy with a magnetic susceptibility in the range from −13 ppm to −5 ppm is an Au—Pt alloy.
The medical image guidance marker according to the present invention is preferably such that the Au—Pt alloy contains Pt at a concentration of not less than 34 mass % and not more than 36 mass % with the balance being Au, and the Au—Pt alloy has a single-phase α structure in which the ratio (X/Y) of the peak intensity (X) of Pt (111) planes to the peak intensity (Y) of Au (111) planes is 0.01 or less in an X-ray diffraction analysis.
Alternatively, the medical image guidance marker according to the present invention is preferably such that the Au—Pt alloy contains Pt at a concentration of not less than 24 mass % and less than 34 mass % with the balance being Au, the Au—Pt alloy has at least a material structure in which a Pt-rich phase having a higher Pt concentration than an α phase is distributed in an α-phase matrix, the Pt concentration in the Pt-rich phase is 1.2 to 3.8 times higher than the Pt concentration in the α phase, and the area ratio of the Pt-rich phase is 1% to 22% in any cross section.
The present invention can provide a medical image guidance marker to be placed in a body, adapted to be applicable to at least all three types of imaging modalities, namely, MRI, ultrasound, and CT, and to minimize the occurrence of artifacts. The medical image guidance marker of the present invention can be particularly suitably used for image-guided therapy for prostate cancer.
The medical image guidance marker according to the present invention will be described with reference to examples. It is to be noted, however, that the present invention is by no means limited to or restricted by the following examples.
The medical image guidance marker of the present invention is made of an alloy with a magnetic susceptibility in the range from −13 ppm to −5 ppm. In order to suppress the occurrence of artifacts, it is important that the magnetic susceptibility (volume magnetic susceptibility) of the material approximate to the magnetic susceptibility of a biological tissue. This does not mean that the magnetic susceptibility of the material should be simply lowered. The magnetic susceptibility of a biological tissue is determined mainly depending on the magnetic susceptibility of water as its main component. The magnetic susceptibility of water is −9 ppm. The present invention enables the reduction of artifacts by using, as the material of the medical image guidance marker, an alloy with a magnetic susceptibility of ±4 ppm relative to the magnetic susceptibility of water, i.e., an alloy with a magnetic susceptibility in the range from −13 ppm to −5 ppm. The term “magnetic susceptibility” as used herein means the volume magnetic susceptibility measured using a superconducting quantum interference device (SQUID) system (7T-SQUID fluxmeter manufactured by Quantum Design Japan, Inc.) at a measurement temperature of 37° C.
However, it was found that the occurrence of artifacts cannot be suppressed sufficiently merely by optimizing the material, and the degree of the occurrence of artifacts also varies depending on the shape of the marker. The inventors of the present invention found that the degree of the occurrence of artifacts differ between the case where a marker has a solid rod shape and the case where a marker has a hollow coil shape that is formed by winding a thin wire, even though their outer shapes are both cylindrical. Further, the inventors found that the pitch p of the coil (turn-to-turn spacing) also affects the occurrence of artifacts. Based on these findings, the inventors succeeded in providing a medical image guidance marker to be placed in a body, adapted to be applicable to at least all three types of imaging modalities, namely, MRI, ultrasound, and CT, and to minimize the occurrence of artifacts.
The shape of the medical image guidance marker of the present invention is specifically as follows: a wire made of a material with a magnetic susceptibility in the above-described range and having a wire diameter d of not less than 0.15 mm and not more than 0.45 mm is formed into a shape of a coil having a coil diameter D of not less than 0.55 mm and not more than 1.20 mm and a pitch p of not less than 0.3 mm and not more than 1.5 mm, and the pitch p is not less than 1.8 times and not more than 4 times the wire diameter d of the wire. The pitch p is preferably not less than 2 times and not more than 3.5 times the wire diameter d, and more preferably not less than 2 times and not more than 3 times the wire diameter d. The wire diameter d is preferably not less than 20% and not more than 40% of the coil diameter D. When the medical image guidance marker of the present invention is used for, for example, the prostate, the shape of the medical image guidance marker is preferably as follows: a wire having a wire diameter d of not less than 0.2 mm and not more than 0.3 mm is formed into a shape of a coil having a coil diameter D of not less than 0.6 mm and not more than 1.0 mm and a pitch p of not less than 0.5 mm and not more than 0.8 mm.
In conventionally used coil-shaped markers, a coil shape is formed by winding a wire in such a manner that adjacent wire turns are in close contact with each other with no gap being formed between adjacent wire turns. In other words, the pitch p of the coil is substantially equal to the wire diameter d of the wire. In contrast, in the medical image guidance marker of the present invention, the pitch p is set to be larger than the wire diameter d, thereby providing a gap between adjacent wire turns of the coil. As will be described below, it was found that, even if the wire is formed of the same material, the occurrence of artifacts (acoustic shadows) in ultrasound images can be suppressed when adjacent wire turns are provided so as to be spaced apart from each other rather than being in close contact with each other. The pitch p of the coil is particularly preferably not less than 0.6 mm and not more than 0.7 mm.
The coil length L can be selected as appropriate depending on an organ in which the medical image guidance marker is to be implanted. In particular, when the medical image guidance marker is used for the prostate, the coil length L is preferably not less than 6 mm and not more than 7 mm. When the marker is used for the prostate, owing to the nature of the tissue around a site to place the marker, the marker may move in the tissue if the length thereof is too short. On this account, the coil length L is preferably not less than 6 mm and not more than 7 mm from the viewpoint of achieving the positional stability. Examples of an organ in which the marker of the present invention is to be implanted include the prostate, lung, liver, gallbladder, kidney, pancreas, and breast. The marker of the present invention is readily available for the prostate.
The alloy with a magnetic susceptibility in the range from −13 ppm to −5 ppm is preferably an Au—Pt alloy. An Au—Pt alloy is a suitable material in terms of capability of allowing artifact-free imaging by MRI. Since gold (Au) alone is too soft to be formed into a predetermined coil shape, an Au—Pt alloy containing a proper amount of Pt is preferable also from the viewpoint of handleability.
The Au—Pt alloy is preferably an alloy disclosed in Japanese Patent No. 5550027, namely, an alloy that contains Pt at a concentration of not less than 34 mass % and not more than 36 mass % with the balance being Au and has a single-phase a structure in which the ratio (X/Y) of the peak intensity (X) of Pt (111) planes to the peak intensity (Y) of Au (111) planes is 0.01 or less in an X-ray diffraction analysis.
Alternatively, the Au—Pt alloy is preferably an alloy disclosed in Japanese Patent No. 5582484, namely, an alloy that contains Pt at a concentration of not less than 24 mass % and less than 34 mass % with the balance being Au and has at least a material structure in which a Pt-rich phase having a higher Pt concentration than an α phase is distributed in an α-phase matrix, the Pt concentration in the Pt-rich phase is 1.2 to 3.8 times higher than the Pt concentration in the α phase, and the area ratio of the Pt-rich phase is 1% to 22% in any cross-section.
Such Au—Pt alloys are favorable in terms of properties required for alloys for medical use, such as biocompatibility, corrosion resistance, and workability, and also have a magnetic susceptibility suitable for use as a material aiming at artifact-free imaging. As described above concerning a coil shape, the occurrence of artifacts (acoustic shadows) is reduced by providing a gap between adjacent wire turns. This, on the other hand, reduces the physical strength derived from the shape. However, since a marker formed using an alloy made of a material containing platinum can have an increased strength as compared with, for example, a coil-shaped marker made of Au alone, the marker can have a sufficient strength for intended use of the present invention even when the marker is in the above-described desired shape.
Several types of markers for external-beam radiotherapy have been put on the market, and they are all made of gold (Au). These markers are placed in a body for the purpose of acquiring positional information in pre-treatment CT imaging, and they are placed in a peripheral portion of a cancer lesion, for example. The reason for this is that, if the markers are placed in a central portion of the cancer lesion, the cancer lesion cannot be observed owing to artifacts caused by the markers. In contrast, the medical image guidance marker of the present invention eliminates the necessity of considering the influence of artifacts. Accordingly, it can be placed in a central portion of a cancer lesion and can be used to directly observe treatment progress or to specify a target site for treatment. Although the target site for treatment also can be specified using conventional markers, it is necessary to place them in several sites around the cancer lesion and identify the positional relationship between each marker and the cancer lesion. Accordingly, multiple punctures are required in order to place the markers. In contrast, the medical image guidance marker of the present invention may be placed directly at a target site. Since the medical image guidance marker need only be placed at one site, the medical image guidance marker is also advantageous in that the number of punctures can be reduced, whereby the burden on a patient can be alleviated.
The medical image guidance marker of the present invention has a shape that smoothly passes through a 16- to 20-gauge puncture needle for image guidance. The surface of the medical image guidance marker of the present invention can maintain a smooth state when the surface of an alloy wire having undergone a wire-drawing process is used as it is. When the surface of the medical image guidance marker is in this state, the insertion resistance at the time of puncture insertion of the marker into a body can be reduced as much as possible. Alternatively, fine irregularities may be provided on the surface of the medical image guidance marker by subjecting the surface of an alloy wire before being formed into a coil shape or the surface of a coil obtained after coil processing of the alloy wire to shot peening, sand blasting, or the like. When the surface of the medical image guidance marker is in this state, the insertion resistance at the time of puncture insertion of the marker increases. However, this can bring about an anchoring effect to prevent unintended movement of the medical image guidance marker within a tissue after the marker is placed in a body. Moreover, in a B-mode (tomographic) ultrasound image, the fine irregularities provided on the surface increase diffuse reflection of echoes, thereby enabling improved visualization. As described above, the medical image guidance marker of the present invention, which is in the form of a coil with a gap being provided between adjacent wire turns, can suppress the occurrence of acoustic shadows to the lowest possible level. Accordingly, it can serve as an indispensable marker when performing a puncture procedure under the guidance of ultrasound imaging while using DICOM data of MRI images, which are becoming more and more widespread in clinical practice, in combination.
The medical image guidance marker of the present invention is applicable not only to external-beam radiotherapy but also to targeted therapy that targets a cancer lesion, such as active surveillance. Further, in conventional external-beam radiotherapy for prostate cancer using X-rays or particle rays, the medical image guidance marker of the present invention can also be used for the purpose of position adjustment using a cone-beam CT system.
CT Images
Marker A was made of an Au-30Pt alloy. Marker A had a wire diameter of 0.2 mm, a coil diameter D of 0.8 mm, and a coil pitch p of 0.6 mm.
Marker B was made of an Au-30Pt alloy. Marker B had a wire diameter of 0.2 mm, a coil diameter D of 0.8 mm, and a coil pitch p of 0.7 mm.
“VISICOIL Marker (Pre-loaded)” VC-076-010-PL 0.75×10 mm (manufactured by Sceti Medical Labo K. K.) was used as Marker C.
This marker is made of Au. The coil diameter D is 0.75 mm, and adjacent wire turns in this coil are in close contact with each other.
“ACCULOC gold marker” MTNW887872 18 G×20 cm 0.9×3 mm (manufactured by CIVCO) was used as Marker D.
This marker is made of Au. The marker is a cylindrical marker having a diameter of 0.9 mm and a length of 3 mm.
The Au-30 Pt alloys used in Examples 1 and 2 and also in Example 3 to be described below were Au—Pt alloys having a Pt concentration of 30 mass % and having undergone a heat treatment at 800° C. for 24 hours according to the method described in Japanese Patent No. 5582484. The alloys in the production lot used in these examples had a magnetic susceptibility of −7 ppm. The magnetic susceptibility of Au is −34 ppm.
In
MRI Images
Ultrasound Images 1
Marker F was made of an Au-30Pt alloy. Marker F had a wire diameter d of 0.3 mm, a coil diameter D of 0.8 mm, and a coil pitch p of 0.6 mm.
“ACCULOC gold marker” (manufactured by CIVCO) was used as Marker E.
This marker is made of Au. The marker is a cylindrical marker having a diameter of 1.2 mm and a length of 3 mm.
It can be seen that the markers of Example 3 and Comparative Examples 2 and 3 were all clearly recognizable in the ultrasound images. In
As markers of other comparative examples, two Au markers “Gold Anchor (trade name)” manufactured by Naslund Medical were provided. They are compatible with a 25-gauge needle, and one was 10 mm in length (Comparative Example 6, GA200-10) and the other was 20 mm in length (Comparative Example 7, GA200-20). Ultrasound images of these markers were examined. These markers have a linear shape before being placed in a body, but they are rounded when placed in a body, thereby turning into a small sphere (0.75 mm in diameter). It was extremely difficult to recognize the positional information of these markers in such a spherical state in the ultrasound images.
Ultrasound Images 2
Marker G was made of an Au-30Pt alloy. Marker G had a wire diameter of 0.2 mm and a coil diameter D of 0.8 mm. The coil pitch p was 0.2 mm, and adjacent wire turns in this coil were in close contact with each other.
Marker H was made of an Au-30Pt alloy. Marker H had a wire diameter d of 0.3 mm and a coil diameter D of 0.8 mm. The coil pitch p was 0.3 mm, and adjacent wire turns in this coil were in close contact with each other.
The markers of Example 1 and Comparative Examples 4 and 5 were made of the same material. Accordingly, it can be seen that the difference in the degree of acoustic shadows was caused by the difference in the coil pitch p of these markers. In the case where the adjacent wire turns of the coil were in close contact with each other (Comparative Examples 4 and 5), artifacts (portions with streak-like acoustic shadows) resulting from multiple echoes were observed at levels deeper than the markers. It can be seen that, by increasing the pitch p relative to the wire diameter d to provide a gap between adjacent wire turns of the coil as in Example 1 (Marker A), the occurrence of artifacts (acoustic shadows) in the ultrasound images was suppressed.
Animal Experiment
An animal experiment was performed using dogs. Dogs were selected for the experiment because the canine prostate is very similar to the human prostate and ultrasound-guided puncture for the canine prostate and the human prostate can be carried out in exactly the same manner. The details of the animals used in the experiment were as follows.
Animal species: dog
Breed: beagle
Sex: male
Age: 63 to 82 months
Number of animals used: five dogs
Weight range of dogs during experiment: 9.55 to 10.90 kg
The following markers were used as medical image guidance markers of the present invention.
A medical image guidance marker of Example 4 was made of an Au-30Pt alloy and had a wire diameter d of 0.3 mm, a coil diameter D of 0.8 mm, and a coil pitch p of 0.7 mm.
A medical image guidance marker of Example 5 was made of an Au-30Pt alloy and had a wire diameter d of 0.3 mm, a coil diameter D of 0.8 mm, and a coil pitch p of 0.9 mm.
The Au-30 Pt alloys used in Examples 4 and 5 were Au—Pt alloys having a Pt concentration of 30 mass % and having undergone a heat treatment at 800° C. for 24 hours according to the method described in Japanese Patent No. 5582484. The alloys in the production lot used in these examples had a magnetic susceptibility of −6.3 ppm.
Anesthesia
Each dog underwent induction of anesthesia with intravenous injection of 22.5 mg/kg of thiamylal sodium (the dose thereof was increased or decreased depending on the anesthetized state, 17 to 23 mg/kg). Thereafter, a tracheal cannula was inserted to the respiratory tract of the dog, and the dog was artificially ventilated using an animal ventilator manufactured by ACOMA Medical Industry Co., Ltd. The dog was then anesthetized by inhalation of a mixed gas (Air:O2=3:0.2 as a general guideline) and 2.0% isoflurane (ISOFLURANE Inhalation Solution “Pfizer” manufactured by Mylan Inc.).
Weight of Prostate
The weights of the prostates of the five dogs were as follows.
Dog 1: 29.4 g
Dog 2: 20.6 g
Dog 3: 14.7 g
Dog 4: 11.1 g
Dog 5: 17.1 g
Placement of Markers
The medical image guidance markers of the present invention and the conventional markers were placed in the right and left lobes of the prostate of each dog in a manner to be described below.
An attempt was made to place two markers of Example 4 (the coil pitch: 0.7 mm) in each lobe of the prostate. However, the two markers placed in the right lobe were in close proximity to each other. Thus, one additional marker was placed at a position apart from the above-described two markers. In the left lobe, two markers of Example 4 were placed, as originally intended.
Two markers of Example 5 (the coil pitch: 0.9 mm) were placed in each lobe of the prostate.
One marker of Example 4 (the coil pitch: 0.7 mm) and one marker of Example 5 (the coil pitch: 0.9 mm) were placed in the right lobe of the prostate. Two markers of Comparative Example 2 (“ACCULOC gold marker” MTNW887872 18G×20 cm 0.9×3 mm (manufactured by CIVCO)) were placed in the left lobe of the prostate.
One marker of Example 4 (the coil pitch: 0.7 mm) and one marker of Example 5 (the coil pitch: 0.9 mm) were placed in the right lobe of the prostate. Two markers of Comparative Example 1 (“VISICOIL Marker (pre-loaded)” VC-076-010-PL 0.75×10 mm (manufactured by Sceti Medical Labo K. K.) were placed in the left lobe of the prostate.
One marker of Example 4 (the coil pitch: 0.7 mm) and one marker of Example 5 (the coil pitch: 0.9 mm) were placed in the right lobe of the prostate. Two markers of Comparative Example 6 (“Gold Anchor” GA200-10 (manufactured by Naslund Medical)) were placed in the left lobe of the prostate.
Results of Ultrasonography
None of the five markers suffered from acoustic shadow interference.
None of the four markers suffered from acoustic shadow interference, and it seemed that the result of ultrasonography obtained in this case did not differ from the result of ultrasonography obtained when the markers of Example 4 with a coil pitch of 0.7 mm were used.
In the left lobe of the prostate where the markers of Comparative Example 2 were placed, distinct acoustic shadows were observed on the markers.
The result of ultrasonography for the left lobe of the prostate where the markers of Comparative Example 1 were placed was equivalent to the result of ultrasonography obtained when the markers of Examples 4 and 5 were used in terms of the occurrence of acoustic shadows.
The markers of Comparative Example 6, which were placed in the left lobe of the prostate, were indefinitely localized (strong echoes indicating the pinpoint positions of the markers were not depicted, and high echo areas in a spherical shape were depicted).
Results of MRI Scan
The results of MRI scan were evaluated using a spin echo method. This is because T1 and T2 images depict needle tracts and hematomas around the needle tracts.
In the cases where the markers of Example 4 and 5 were used, almost no artifacts were observed.
In the cases where the markers of Comparative Examples 2 and 6 were used, distinct artifacts were depicted. In the case where the markers of Comparative Example 1 were used, artifacts were observed although these artifacts were less pronounced than those observed when the markers of Comparative Examples 2 and 6 were used.
The results of the above-described animal experiment demonstrate that the medical image guidance marker of the present invention exhibits good visibility after being placed and also causes no positional displacement after being placed. The results of the MRI scan demonstrate that, although the markers of the comparative examples caused pronounced artifacts even when a single one of them was placed in a target site, the medical image guidance markers of the present invention caused no artifacts even when two or more of them were placed in different sites in a target organ.
The medical image guidance marker of the present invention enables more detailed observation or diagnosis in a less invasive manner, and this, in turn, further enables more precise therapy.
| Number | Date | Country | Kind |
|---|---|---|---|
| 2019-128620 | Jul 2019 | JP | national |
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/JP2020/023063 | 6/11/2020 | WO |
