Hemoglobin concentration measuring system, transvaginal probe, accessories and hemoglobin concentration measuring method

Abstract

The hemoglobin concentration measuring system includes a transvaginal probe, a display unit, and a concentration calculating unit, wherein the transvaginal probe has: an ultrasonic transmitting and receiving unit capable of transmitting ultrasonic waves to biological tissues and receiving ultrasonic echoes reflected from the biological tissues; a light irradiating unit capable of emitting light including specific multiple wavelength components in a wavelength range from visible light to near-infrared light in a direction parallel to a scanning plane of the ultrasonic waves transmitted by the ultrasonic transmitting and receiving unit; and a light receiving unit capable of receiving reflected light or transmitted light emitted from the light irradiating unit and reflected by the biological tissues or transmitted through the biological tissues and propagated in a direction parallel to the above-mentioned scanning plane, wherein the display unit is capable of displaying an ultrasonic image including an image of an ovarian cyst based on the ultrasonic echoes received by the ultrasonic transmitting and receiving unit, and the concentration calculating unit calculates the hemoglobin concentration in the cystic fluid retained in the ovarian cyst based on the spectral spectrum of the reflected light or transmitted light from the ovarian cyst received by the light receiving unit.

Description

Technical Field

[0001] The present invention relates to a technique for measuring the hemoglobin concentration in the cyst fluid of an endometrial ovarian cyst in vivo. Background Art

[0002] Endometrial ovarian cyst, a type of endometriosis, is a benign ovarian cyst also known as a "chocolate cyst," and is a cyst formed by blood accumulation due to bleeding from endometriosis that occurs in the ovary.

[0003] In addition, ovarian cancer caused by endometriosis is collectively referred to as endometriosis-associated ovarian cancer (EAOC). In epidemiology, patients over 44 years old with cysts larger than 84 mm in diameter and whose cysts grow rapidly in a short period of time have a high risk of cancer, so ovarian removal surgery is currently recommended.

[0004] As a technique related to determination of the malignancy of endometrial ovarian cysts, Non-Patent Document 1 discloses the correlation between the malignancy of endometrial ovarian cysts and the concentration of biomarkers.

[0005] In addition, Patent Document 1 discloses a method for determining the possibility of an endometrial ovarian cyst becoming cancerous in a diagnostic device including a determination unit for determining the possibility of canceration, the determination unit including an iron concentration determination unit for determining the iron concentration in the collected endometrial ovarian cyst fluid, and an existence ratio determination unit for determining the existence ratio of methem and oxyheme in the cyst fluid of the endometrial ovarian cyst. In Patent Document 1, as methods for determining the total heme iron concentration in the cyst fluid, Triton-MeOH analytical colorimetric method and high-speed liquid chromatography are exemplified. In addition, as methods for determining the iron concentration in the cyst fluid in the state where the cyst fluid is enclosed in the endometrial ovarian cyst, near-infrared spectroscopy, magnetic resonance spectroscopy (MRS), radiometric analysis, and fluorescent X-ray analysis are exemplified. Furthermore, Patent Document 1 discloses an iron concentration determination unit including a probe having a light-emitting unit and a light-receiving unit having near-infrared light.

[0006] In addition, Patent Document 2 discloses a blood analysis method using near-infrared spectroscopy, which is as follows: light is irradiated from the outside through the blood collection tube or blood collection bag to the blood in the translucent blood collection tube or blood collection bag, and scattered reflected light, scattered transmitted light, or transmitted reflected light from the blood in the blood collection tube or blood collection bag is detected by a light sensor to measure the near-infrared absorption spectrum of the blood, and the measured value is substituted into a calibration curve prepared in advance based on the spectrum measured by the same method, thereby obtaining the chemical composition or physicochemical properties of the blood. In this blood analysis method, the blood in the translucent blood collection tube or blood collection bag is irradiated with near-infrared light with a wavelength of 700nm to 1100nm.

[0007] Patent Document 3 discloses a diagnostic probe for acquiring data for diagnosing endometrial ovarian cysts.

[0008] Non-patent document 2 discloses that a simulated cyst containing a hemoglobin solution of known concentration is irradiated with near-infrared light, the hemoglobin concentration is calculated based on the spectroscopic spectrum of the reflected light, and a multivariate regression equation is constructed using multiple wavelengths based on multivariate analysis.

[0009] [Prior art literature]

[0010] [Patent Document]

[0011] Patent Document 1: Japanese Patent Application Publication No. 2018-163174

[0012] Patent Document 2: Japanese Patent Application Publication No. 2002-122537

[0013] Patent Document 3: Japanese Patent No. 6657438

[0014] [Patent Document]

[0015] Non-patent document 1: C. Yoshimoto et al., "Cyst fluid iron-related compounds as useful markers to distinguish malignant transformation from benign endometriotic cysts", Cancer Biomarkers, vol. 15 (2015), p. 493-499

[0016] Non-patent document 2: "Development of an optical transvaginal probe capable of evaluating the malignancy of endometriosis in a low-invasive manner", Report on the results of research and development of strategic basic technology advancement / collaborative support projects in 2017,<URL:https: / / www.chusho.meti.go.jp / keiei / sapoin / portal / seika / 28fy.htm> , published in October 2018 Summary of the invention

[0017] [Problems to be solved by the invention]

[0018] The malignancy (the possibility of canceration) of endometrial ovarian cysts has been estimated based on the morphological evaluation of ovarian cysts using ultrasonic diagnostic equipment, computed tomography (CT), and magnetic resonance imaging (MRI). However, as can be seen from the fact that 1% of endometrial ovarian cysts become cancerous in the pathological diagnosis results after oophorectomy, it is actually difficult to distinguish between benign endometrial ovarian cysts and cancerous endometrial ovarian cysts based on such morphological evaluation.

[0019] As a method for identifying cancerous parts, there is a contrast MRI examination in which a contrast agent is administered to the patient. However, this method places a heavy burden on the patient and there is also a risk of side effects of the contrast agent. In addition, there is the problem that it cannot be implemented through conventional external diagnosis and treatment. Therefore, contrast MRI examinations cannot be performed frequently, and depending on the frequency of the examination, cases of cancer may be missed.

[0020] As such, there is currently no method that can easily and non-invasively determine the malignancy of endometrial ovarian cysts with high accuracy. Therefore, under the current circumstances, for patients diagnosed with endometrial ovarian cysts, it is difficult to perform treatments corresponding to the degree of progression of the disease by regular examinations. As a result, in the case of endometrial ovarian cysts, although they have not yet become cancerous, many patients undergo surgical treatment to remove the endometrial ovarian cysts together with the ovaries, considering the possibility of canceration in the future.

[0021] In response to such a problem, according to Patent Document 1, by using hemoglobin in cyst fluid as a biomarker, the malignancy of endometrial ovarian cysts can be determined more easily and accurately than before. In addition, if the hemoglobin concentration in cyst fluid can be measured non-invasively in the location (in vivo), the burden on patients can be reduced.

[0022] The concentration of a specific component in a liquid can be measured contactlessly by spectroscopy using a spectral spectrum of reflected light reflected from the liquid or transmitted light passing through the liquid (for example, refer to Patent Document 2). However, the cyst fluid is retained in an amorphous and non-uniform tissue such as interstitial cells or visceral fat in the body. Therefore, even if the ovarian cyst is irradiated with light in the body in order to non-invasively measure the hemoglobin concentration in the cyst fluid, the noise in the spectral spectrum obtained thereby may become very large due to the presence of tissues such as interstitial cells or visceral fat. In the case of measuring the hemoglobin concentration by spectroscopy based on such a spectral spectrum, sufficient measurement accuracy cannot be obtained compared to the case of collecting cyst fluid from an ovarian cyst and measuring the concentration in vitro.

[0023] In contrast, in non-patent document 2, since a multivariate regression equation is constructed based on the measured values ​​obtained from an experiment in which a simulated cyst is irradiated with near-infrared light, the influence of the above-mentioned tissues such as interstitial cells or visceral fat can be reduced even when the hemoglobin concentration in cyst fluid is measured in vivo.

[0024] However, in order to measure the hemoglobin concentration in the cyst fluid in vivo, it is necessary to reliably irradiate light onto the cyst fluid as the measurement object. In this regard, in Patent Document 3 and Non-Patent Document 2, ultrasonic images are used to confirm the location of ovarian cysts, but the detailed structure is unclear, making it difficult to reliably irradiate light onto the measurement object and perform stable measurement.

[0025] The present invention has been made in view of the above-mentioned problems, and its object is to provide a hemoglobin concentration measurement system, a transvaginal probe, an accessory, and a hemoglobin concentration measurement method that can non-invasively and stably measure the hemoglobin concentration in the cyst fluid retained in an ovarian cyst in a living body.

[0026] [Technical means for solving technical problems]

[0027] In order to solve the above-mentioned technical problems, a hemoglobin concentration measurement system as one embodiment of the present invention includes: a transvaginal probe, which has: an ultrasonic transmitting and receiving unit capable of transmitting ultrasonic waves to biological tissues and capable of receiving ultrasonic echoes reflected from the biological tissues, a light irradiation unit capable of emitting light including specific multiple wavelength components in a wavelength range from visible light to near-infrared light in a direction parallel to a scanning plane of the ultrasonic waves transmitted by the ultrasonic transmitting and receiving unit, and a light receiving unit capable of receiving reflected light or transmitted light emitted from the light irradiation unit and reflected by biological tissues or transmitted through biological tissues and propagated in a direction parallel to the scanning plane; a display unit capable of displaying an ultrasonic image including an image of an ovarian cyst based on the ultrasonic echoes received by the ultrasonic transmitting and receiving unit; and a concentration calculation unit capable of calculating the concentration of hemoglobin in cystic fluid retained in the ovarian cyst based on the spectral spectrum of the reflected light or the transmitted light from the ovarian cyst received by the light receiving unit.

[0028] In the above-mentioned hemoglobin concentration measuring system, the ultrasonic transmitting and receiving unit may transmit ultrasonic waves in a manner of convexly scanning biological tissue, and the light irradiation unit may be arranged in a manner capable of emitting the light in a direction parallel to the transmission direction of the ultrasonic waves at the center of the convex scanning surface.

[0029] In the above hemoglobin concentration measurement system, the light irradiation unit and the light receiving unit may be arranged on opposite sides of each other with the ultrasonic wave transmitting and receiving unit interposed therebetween.

[0030] In the above hemoglobin concentration measuring system, the light irradiating section and the light receiving section may be arranged so that a line connecting an end surface of the light irradiating section and an end surface of the light receiving section is orthogonal to a scanning direction of the ultrasonic wave transmitted from the ultrasonic wave transmitting and receiving section.

[0031] In the above hemoglobin concentration measuring system, a distance between centers of an end surface of the light irradiation section and an end surface of the light receiving section may be not less than 10 mm and not more than 31 mm.

[0032] In the above-mentioned hemoglobin concentration measurement system, the ultrasonic transmitting and receiving part may be arranged on an ultrasonic probe for transvaginal use, and the light irradiation part and the light receiving part may be installed on a bracket, and the bracket covers the insertion part of the ultrasonic probe which is inserted into the vagina, and the light irradiation part and the light receiving part can be removed relative to the ultrasonic probe together with the bracket.

[0033] In the above-mentioned hemoglobin concentration measurement system, the concentration calculation unit can also obtain the measured values ​​of the absorbance at the specific multiple wavelengths, substitute the measured values ​​of the absorbance into a pre-obtained specified formula representing the relationship between the absorbance at the specific multiple wavelengths and the concentration of hemoglobin, thereby calculating the concentration of the hemoglobin.

[0034] In the above-mentioned hemoglobin concentration measurement system, the plurality of wavelength components may include at least a wavelength component in the visible light region.

[0035] In the above-mentioned hemoglobin concentration measurement system, the plurality of wavelength components may be wavelength components in the visible light region.

[0036] In the above hemoglobin concentration measurement system, the specific plurality of wavelengths may include at least two or more wavelengths selected from 580 nm, 590 nm, 640 nm, 680 nm, and 762 nm.

[0037] The hemoglobin concentration measurement system may further include a determination unit that determines whether the hemoglobin concentration calculated by the concentration calculation unit corresponds to one of the categories of malignancy of the endometrial ovarian cyst that are previously associated with the hemoglobin concentration.

[0038] As another embodiment of the present invention, a transvaginal probe is a transvaginal probe used in a hemoglobin concentration measuring system for measuring the concentration of hemoglobin in cystic fluid retained in an ovarian cyst, and comprises: an ultrasonic transmitting and receiving unit capable of transmitting ultrasonic waves to a living tissue and receiving ultrasonic echoes reflected from the living tissue; a light irradiating unit capable of emitting light including specific multiple wavelength components in a wavelength range from visible light to near-infrared light in a direction parallel to a scanning plane of the ultrasonic waves transmitted by the ultrasonic transmitting and receiving unit; and a light receiving unit capable of receiving reflected light or transmitted light emitted from the light irradiating unit and reflected by the living tissue or transmitted through the living tissue and propagated in a direction parallel to the scanning plane, wherein when an ultrasonic image including an image of an ovarian cyst is displayed based on the ultrasonic echoes received by the ultrasonic transmitting and receiving unit, the light irradiating unit emits light toward the ovarian cyst and the light receiving unit receives the reflected light or transmitted light from the ovarian cyst.

[0039] As an accessory of another scheme of the present invention, it is an accessory that can be installed on a transvaginal ultrasonic probe provided with an ultrasonic transmitting and receiving unit that can transmit ultrasonic waves to biological tissue and can receive ultrasonic echoes reflected from the biological tissue, comprising: a bracket that covers the insertion portion of the ultrasonic probe that is inserted into the vagina; a light irradiation unit that can emit light containing specific multiple wavelength components in a wavelength region from visible light to near-infrared light, and is installed on the bracket in a manner that allows the light to be irradiated in a specified direction when the ultrasonic probe covered with the bracket is inserted into the vagina; and a light receiving unit that can receive the light, and is installed on the bracket in a manner that allows the reflected light or the transmitted light that is emitted from the light irradiation unit and reflected by the biological tissue or passes through the biological tissue and propagates from a specified direction when the ultrasonic probe covered with the bracket is inserted into the vagina.

[0040] In the above-mentioned accessory, it may also be that the light irradiation unit is installed on the bracket in a manner such that it can irradiate the light in a direction parallel to a scanning plane of the ultrasonic wave transmitted by the ultrasonic wave transmitting and receiving unit; and the light receiving unit is installed on the bracket in a manner such that it can receive the reflected light or the transmitted light propagating from a direction parallel to the scanning plane.

[0041] A hemoglobin concentration measuring method as another embodiment of the present invention includes: an ultrasonic image display step of transmitting ultrasonic waves to a living tissue through the vagina, receiving ultrasonic echoes reflected from the living tissue, and displaying an ultrasonic image including an image of an ovarian cyst based on the ultrasonic echoes; a light irradiation step of emitting light including specific multiple wavelength components in a wavelength range from visible light to near-infrared light in a direction parallel to a scanning plane of the ultrasonic waves transmitted in the ultrasonic image display step; a light receiving step of receiving reflected light or transmitted light emitted in the light irradiation step and reflected by the living tissue or transmitted through the living tissue and propagated in a direction parallel to the scanning plane; and a concentration calculation step of calculating the concentration of hemoglobin in the cystic fluid retained in the ovarian cyst based on the spectral spectrum of the reflected light or the transmitted light received from the ovarian cyst in the light receiving step.

[0042] [Effects of the invention]

[0043] According to the present invention, since light is emitted in a predetermined direction relative to the scanning surface of ultrasound, it is possible to reliably irradiate light to living tissues by referring to ultrasound images, and receive reflected light or transmitted light thereof. Therefore, it is possible to non-invasively and stably measure the hemoglobin concentration in the cystic fluid held in the ovarian cyst in the living body. BRIEF DESCRIPTION OF THE DRAWINGS

[0044] Figure 1This is a table showing the confirmed diagnosis and hemoglobin concentration after oophorectomy.

[0045] Figure 2 It is a graph showing the hemoglobin concentration and cutoff value of the non-cancer group and the cancer group.

[0046] Figure 3 This is a flowchart showing the method for measuring the biomarker concentration according to the first embodiment of the present invention.

[0047] Figure 4 It means to find out Figure 3 Flow chart of the method showing the calculation formula used in the concentration calculation step.

[0048] Figure 5 This is a block diagram illustrating a schematic configuration of a hemoglobin concentration measurement system according to the first embodiment of the present invention.

[0049] Figure 6 It is a top view schematically showing the measurement optical system used in Example 1-1.

[0050] Figure 7 This is a graph showing the second derivative of the spectral spectrum in Example 1-1.

[0051] Figure 8 This is a graph showing the correlation between the directly measured concentration and the calculated concentration (when all wavelengths are used) of hemoglobin in Example 1-1.

[0052] Fig. 9 This is a graph showing the correlation between the directly measured concentration and the calculated concentration (when 12 wavelengths are used) of hemoglobin in Example 1-2.

[0053] Fig.10 This is a graph showing the correlation between the directly measured concentration and the calculated concentration (when two wavelengths are used) of hemoglobin in Example 1-3.

[0054] Fig.11 This is a table showing the wavelengths and correlation coefficients used in creating the regression equations in Examples 1-4.

[0055] Fig.12 This is a graph showing the second derivative of the spectral spectrum in Example 2-1.

[0056] Fig.13 This is a graph showing the correlation between the directly measured concentration and the calculated concentration (when all wavelengths are used) of hemoglobin in Example 2-1.

[0057] Fig.14This is a graph showing the correlation between the directly measured concentration and the calculated concentration (when two wavelengths are used) of hemoglobin in Example 2-2.

[0058] Fig.15 This is a plan view schematically showing the tip portion of the probe used in Example 3.

[0059] Fig.16 This is a graph showing the correlation between the directly measured concentration and the calculated concentration of hemoglobin in Example 3.

[0060] Fig.17 It is a side view schematically showing a transvaginal probe according to a second embodiment of the present invention.

[0061] Fig.18 yes Fig.17 A top view of a transvaginal probe is shown.

[0062] Fig.19 yes Fig.17 Magnified view in the X direction.

[0063] Fig. 20 This is a schematic diagram for explaining the relationship between an ultrasonic image and the irradiation direction of light.

[0064] Fig.21 This is a graph showing the correlation between the directly measured hemoglobin concentration and the calculated concentration (when two wavelengths are used) in Example 4. DETAILED DESCRIPTION

[0065] Hereinafter, the measurement method, hemoglobin concentration measurement system, transvaginal probe, accessory, and hemoglobin concentration measurement method according to the embodiments of the present invention will be described with reference to the accompanying drawings. In addition, the present invention is not limited to these embodiments. In addition, in the description of each of the drawings, the same reference numerals are attached to the same parts for representation.

[0066] The drawings referred to in the following description only roughly represent the shapes, sizes, and positional relationships to the extent that the contents of the present invention can be understood. That is, the present invention is not limited to the shapes, sizes, and positional relationships illustrated in the drawings. In addition, the drawings sometimes include parts with different dimensional relationships or ratios. In this specification, "A to B" indicating a numerical range means "above A and below B" unless otherwise specified.

[0067] In the following embodiments, hemoglobin in cyst fluid retained in endometrial ovarian cysts is used as an example of a biomarker to be measured, but the method for measuring the concentration of a biomarker of the present invention is not limited to the concentration of hemoglobin in cyst fluid in ovarian cysts, and can be applied to the case of measuring the concentration of various components of a liquid retained in a living tissue when the liquid is retained in the living tissue.

[0068] The cyst fluid of endometrial ovarian cyst refers to the fluid accumulated in the endometrial ovarian cyst. Hemoglobin in the cyst fluid can be used as a biomarker to determine the possibility of endometrial ovarian cyst becoming cancerous (i.e., malignancy). As the subject, there is no particular limitation as long as it is an organism that may develop endometrial ovarian cyst, and all mammals are the subjects.

[0069] The malignancy of endometrial ovarian cysts can be determined based on the knowledge that the concentration of hemoglobin contained in the cyst fluid of cancerous endometrial ovarian cysts is significantly lower than the concentration of hemoglobin in the cyst fluid of benign endometrial ovarian cysts.

[0070] First, the correlation between the hemoglobin concentration in cyst fluid and the malignancy of endometrial ovarian cysts will be described based on statistical analysis of the measurement results of hemoglobin concentrations of clinical samples.

[0071] The inventors of the present application measured the hemoglobin concentration in cyst fluid provided by patients who had undergone ovarian removal surgery, and clarified the correlation between the hemoglobin concentration in the cyst fluid and the malignancy of the cyst. Figure 1 This is a table showing the postoperative diagnosis and hemoglobin concentration in some cases. In addition, the hemoglobin concentration was measured as follows: using the Metallogenic LS Heme Analysis Kit (manufactured by Metallogenics Co., Ltd.), the electronic absorption spectrum was measured by a microplate reader (manufactured by Corona Electric Co., Ltd., model: SH-1200).

[0072] According to the postoperative pathologist's diagnosis, 88 of the 117 cases were diagnosed as non-cancer group and 29 as cancer group. The following table shows the mean value, standard deviation, range, and significance probability (p value) of the measurement results.

[0073] [Table 1]

[0074]

[0075] Mean ± SD

[0076] As shown in Table 1, the average hemoglobin concentration in the non-cancer group was 5.7 g / dL, and the average hemoglobin concentration in the cancer group was 0.9 g / dL, indicating that the hemoglobin concentration in the non-cancer group was significantly higher than that in the cancer group. In addition, the p value was less than 0.001, indicating that there was a clear correlation between the hemoglobin concentration and the degree of malignancy.

[0077] The results were analyzed using ROC curves, and the cutoff value between the cancer group and the non-cancer group was calculated to be 2.0 g / dL. The sensitivity and specificity at this time were 95.4% and 81.1%, respectively. In addition, the positive predictive rate and negative predictive rate when using this cutoff value were 95.4% and 85.7%, respectively.

[0078] Figure 2 This is a graph showing the results of testing the difference in the mean values ​​of hemoglobin concentration in cyst fluid between the non-cancer group and the cancer group using non-parametric analysis (Mann-Whitney U test). Figure 2 The cutoff value is indicated by a dotted line.

[0079] According to the above analysis, when the hemoglobin concentration in the sample is 0.0 to 2.0 g / dL, the possibility of canceration can be determined with a probability of 85.7%.

[0080] In addition, the relationship between the numerical range of hemoglobin concentration and the determination of the malignancy of endometrial ovarian cysts is also recorded in C. Yoshimoto et.al., "Cyst fluid iron-related compounds as useful markers to distinguish malignant transformation from benign endometriotic cysts" (Cancer Biomarkers, vol. 15 (2015), p. 493-499). In this document, the cutoff value is a heme iron concentration of 72.7 mg / dL (see p. 497), which corresponds to a hemoglobin concentration of 2.0 g / dL.

[0081] (First embodiment)

[0082] Figure 3This is a flow chart showing the measurement method of the first embodiment of the present invention. The measurement method of this embodiment is a method for non-invasively measuring the concentration of a biomarker in a liquid retained in a living tissue on site (in vivo) when the liquid is retained in the living tissue. The following is an example of measuring the hemoglobin concentration in the cyst fluid retained in an endometrial ovarian cyst of a subject.

[0083] First, an ultrasonic observation device is used to display an ultrasonic image including an image of a biological tissue as a target, and the position of the biological tissue is confirmed (ultrasonic image display step S1). For example, when measuring the hemoglobin concentration in the cystic fluid held in an ovarian cyst, an ultrasonic probe for transvaginal use is used to display an ultrasonic image including an image of the ovarian cyst.

[0084] Next, the biological tissue holding the liquid is irradiated with light in the wavelength region from visible light to near-infrared light (light irradiation step S2). As the irradiation light, there is no particular limitation as long as it is light containing a specific plurality of wavelength components described later. It can be only visible light, only near-infrared light, or light containing both. The specific plurality of wavelengths is determined according to the formula used in the concentration calculation step S5 described later. For example, in the case of measuring the hemoglobin concentration in the cyst fluid in an ovarian cyst, the irradiation light is preferably light containing at least two wavelength components selected from 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm. The light source that generates the irradiation light is not particularly limited as long as it can irradiate light non-invasively to the organism. For example, a light source composed of a combination of multiple LEDs with different peak wavelengths can be used, or a halogen lamp can be used. In addition, the method of irradiation of light is not particularly limited as long as it is non-invasive to the organism, and can be irradiated vaginally or abdominally. For example, by connecting an optical fiber to a light source and bringing the end of the optical fiber into contact with the organism, light can be irradiated locally on the organism.

[0085] Next, the reflected light reflected by the biological tissue or the transmitted light passing through the biological tissue is received (light receiving step S3). The light receiving component of the reflected light or the transmitted light is not particularly limited as long as it is a non-invasive component capable of detecting the light intensity in the above-mentioned specific multiple wavelengths. As the light receiving component, for example, a light receiving component composed of a plurality of spectroscopic sensors having sensitivity only at a specific wavelength can be used, or a sensor capable of detecting a wavelength of a wide band can be used. In addition, by connecting an optical fiber to these sensors, the end of the optical fiber is brought into contact with the organism, and light from a part of the organism can be received.

[0086] In the light irradiation step S2 and the light receiving step S3, for example, a light irradiation component and a light receiving component may be provided on the transvaginal probe to irradiate light from the vagina and receive reflected light in the vagina. In addition, a light irradiation component and a light receiving component may be provided on the transabdominal probe to irradiate light from the abdominal surface and receive reflected light on the abdominal surface. Alternatively, an irradiation component and a light receiving component may be provided on the transabdominal probe and the transvaginal probe, respectively, to irradiate light from the abdominal surface and receive transmitted light in the vagina, or vice versa.

[0087] Next, based on the light received in the light receiving step S3, the measured values ​​of the absorbance at a specific plurality of wavelengths are obtained (absorbance obtaining step S4). As described above, the specific plurality of wavelengths are determined according to the formula used in the concentration calculation step S5 described later. The absorbance A(λ) at the wavelength (λ) can be calculated by the following formula (1) based on the Lambert-Beer law using the intensity I0 of the irradiated light and the intensity I1 of the reflected light or the transmitted light.

[0088] A(λ)=-log 10 (I1 / I0)…(1)

[0089] Next, the absorbance measurement value obtained in the absorbance acquisition step S4 is substituted into a predetermined formula that represents the relationship between the absorbance at a plurality of specific wavelengths and the concentration of the biomarker, thereby calculating the concentration of the biomarker (concentration calculation step S5). The concentration C of the biomarker is calculated by, for example, substituting the absorbance measurement value obtained in the absorbance acquisition step S4 into a predetermined formula that represents the relationship between the absorbance at a plurality of specific wavelengths and the concentration of the biomarker. n The absorbance A(λ n ) (n = 1 to N, N ≧ 2) as variables. In formula (2), coefficient a n It is preset. In addition, the symbol b is a constant.

[0090] C=a1·A(λ1)+a2·A(λ2)+…+a N ·A(λ N )+b…(2)

[0091] In this way, the concentration C of the biomarker can be obtained non-invasively.

[0092] Next, a method of obtaining the formula used in the concentration calculation step S5 will be described.

[0093] As described above, by measuring the hemoglobin concentration in the cyst fluid, the malignancy of endometrial ovarian cysts can be determined with high accuracy. However, since the cyst fluid is retained in amorphous and uneven biological tissues such as interstitial cells or visceral fat, when the cyst fluid is irradiated with light across the biological tissue (i.e., without invading the biological tissue), the noise becomes very large in the spectral spectrum of its reflected light or transmitted light. Therefore, even if the hemoglobin concentration is measured by a general spectroscopy using the Lambert-Beer law based on a spectral spectrum with large noise like this, sufficient measurement accuracy cannot be obtained. Originally, it is also difficult to determine the optical path length in the organism. That is to say, in a state where the cyst fluid is retained in amorphous interstitial cells, etc., quantitative analysis based on spectroscopy is difficult and unrealistic.

[0094] Therefore, the inventors of the present application have repeatedly conducted in-depth research, prepared simulated biological samples (simulated cysts) that simulate biological tissues such as interstitial cells, repeatedly performed spectroscopic measurements on the simulated biological samples, and analyzed the obtained spectroscopic spectra. As a result, it was thought that the measurement method of this embodiment can measure the concentration of biomarkers with high accuracy by using absorbance at a specific wavelength even if the thickness, composition, water content, and optical path length of biological tissues are different.

[0095] In addition, it was previously believed that visible light has low biological permeability and therefore is difficult to reach the cyst, making it unsuitable for non-destructive inspection. However, the inventors of the present application have discovered that if there is a light quantity that allows visible light to reach the cyst fluid held in the interstitial cells and is sufficient to detect the reflected light or transmitted light, a unique optical signal can be obtained from there. Through the efforts of the inventors of the present application, by using light of a specific wavelength included in the wavelength region from visible light to near-infrared light, the concentration of biomarkers in the cyst fluid held in the endometrial ovarian cyst can be measured non-invasively and with high precision on the spot.

[0096] Figure 4 It means to find out Figure 3 The flowchart of the method of the calculation formula used in the concentration calculation step S5 is shown.

[0097] First, a plurality of simulated biological samples are prepared by covering a transparent container with biological tissue, wherein the container contains a liquid with a known concentration of a biomarker (hemoglobin in this embodiment), and the processing of steps S11 to S13 is repeated for a set number of times for each simulated biological sample. The liquid can be any liquid with a clear hemoglobin concentration, for example, it can be a hemoglobin aqueous solution obtained by dissolving hemoglobin powder in pure water, or it can be cyst fluid collected from a living body. In the latter case, the hemoglobin concentration is measured in advance using a known concentration measurement means such as a spectrophotometer.

[0098] The container for holding the liquid is not particularly limited as long as it is a container formed of a transparent and uniform raw material. Preferably, a transparent capsule chamber or a cuvette used in a general spectrophotometer or the like can be used. In addition, as the biological tissue wrapping the container, commercially available biological tissues such as pork, chicken, or their fat can be used.

[0099] Such a simulated biological sample is irradiated with light in the wavelength range from visible light to near infrared light (step S1). The irradiated light may be only visible light, only near infrared light, or both visible light and near infrared light. In addition, there is no problem even if the irradiated light contains light of a wavelength exceeding the wavelength range from visible light to near infrared light (e.g., ultraviolet light). The light source for generating the irradiated light is not particularly limited, and for example, a halogen lamp or the like may be used.

[0100] Next, the reflected light reflected by the simulated biological sample or the transmitted light passing through the simulated biological sample is received (step S12). Furthermore, the spectral spectrum of the received light is obtained (step S13). The means for receiving the reflected light or the transmitted light and obtaining the spectral spectrum is not particularly limited, and a general spectrometer or a spectral sensor can be used.

[0101] By repeating such steps S11 to S13, a plurality of spectral spectra corresponding to a plurality of simulated biological samples are obtained. Then, based on the obtained plurality of spectral spectra, a plurality of wavelengths where characteristic light signals can be observed are extracted from the wavelength region of the light irradiated in step S11 (step S14). It can be said that the characteristic light signal indicates the presence of a biomarker.

[0102] An example of a wavelength extraction method is described below. First, each spectral spectrum is subjected to a second derivative. The method of second derivative is not particularly limited, and for example, the Savitzky-Golay method can be used. Since the significant difference in the original spectrum appears as a downward peak in the second derivative of the spectrum, the wavelength at which the downward peak appears is extracted. At this time, all downward peaks can be extracted, or a specified number of wavelengths can be selected from the larger peak. Alternatively, the wavelengths of all peaks with a specified value (absolute value) or above can be selected.

[0103] Next, a formula representing the relationship between the absorbance at the multiple wavelengths selected in step S14 and the concentration of the biomarker is obtained (step S15). In detail, based on each of the multiple spectral spectra, the absorbance at the selected multiple wavelengths is obtained, and regression analysis is performed using the obtained absorbance as an explanatory variable and the known concentration of the biomarker in the solution in the simulated biological sample as a response variable. The method of regression analysis is not particularly limited as long as it can perform analysis corresponding to the number of samples (number of measurements) and the number of selected wavelengths. As an example of an applicable regression analysis, PLS analysis (partial least squares regression analysis) as a type of multivariate analysis can be cited.

[0104] In addition, the above-mentioned step S14 is not essential. When step S14 is omitted, in step S15, the same regression analysis may be performed using absorbances at all wavelengths detectable within the wavelength range of the irradiation light.

[0105] The formula thus obtained is not easily affected by factors such as the thickness, composition, and water content of biological tissues, and the difference in optical path length caused by these factors, and can accurately reflect the concentration of the biomarker to be measured. Therefore, the measured value of the absorbance at a specific wavelength obtained by irradiating light to the ovarian cyst via the vagina or abdomen is substituted into the above formula (refer to Figure 3 The concentration calculation step S5) will not be greatly affected by the thickness and composition of the interstitial cells or visceral fat, and the hemoglobin concentration in the cyst fluid retained in the ovarian cyst can be quantitatively and accurately determined.

[0106] Figure 5 This is a block diagram illustrating a schematic configuration of the hemoglobin concentration measurement system according to the present embodiment. Figure 5 The hemoglobin concentration measurement system shown also has a function of determining the malignancy of endometrial ovarian cysts using hemoglobin in cyst fluid as a biomarker. Figure 5 The hemoglobin concentration measuring system 10 shown includes a probe 100 for transvaginal or transabdominal use and a main body 110. The probe 100 and the main body 110 are connected by a cable including an optical fiber and a wire for transmitting an electrical signal.

[0107] The probe 100 comprises: an irradiating section 101, which irradiates the biological tissue of the subject (patient) with light transmitted from the main body 110 via the optical fiber for light transmission; a light receiving section 102, which receives reflected light reflected from the biological tissue or transmitted light passing through the biological tissue and transmits it to the main body 110 via the optical fiber for light reception; and an ultrasonic transmitting and receiving section 103, which transmits ultrasonic waves to the biological tissue and receives ultrasonic echoes reflected from the biological tissue.

[0108] The irradiation unit 101 may be an irradiation unit having an optical system such as a focusing lens provided at the end of an optical fiber. The light receiving unit 102 may be a light receiving unit having an optical system such as a focusing lens provided at the end of an optical fiber for focusing reflected light or transmitted light.

[0109] The ultrasonic wave transmitting and receiving unit 103 is composed of one or more piezoelectric vibrators with electrodes formed at both ends of a piezoelectric body such as a piezoelectric ceramic such as PZT (lead zirconate titanate) or a polymer piezoelectric element such as PVDF (polyvinylidene fluoride). The ultrasonic wave transmitting and receiving unit 103 generates ultrasonic waves based on a driving electrical signal transmitted from the main body 110, receives ultrasonic wave echoes reflected from biological tissues, converts them into electrical signals (ultrasonic wave reception signals), and transmits them to the main body 110.

[0110] The main body 110 includes: a light source 111 that generates light and transmits it to the probe 100; a spectrometer 112 that receives the light transmitted from the probe and performs spectrometry; a drive signal generating unit 113 that generates an ultrasonic drive signal and sends it to the probe 100; an ultrasonic signal processing unit 114 that processes the ultrasonic receiving signal sent from the probe 100; an operation input unit 115; a display unit 116; a storage unit 120; and a control unit 130.

[0111] The light source 111 generates light containing a specific plurality of wavelength components in a wavelength region from visible light to near infrared light. As the light source 111, it is preferred that a light source generates light having good directivity. As an example, the light source 111 generates light containing a component of two or more wavelengths selected from 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm. As the light source 111, a light source composed of a combination of a plurality of LEDs having different peak wavelengths can be used, or a halogen lamp that generates light from ultraviolet light to near infrared light can be used. The light generated by the light source 111 is transmitted to the irradiation unit 101 via an optical fiber.

[0112] The spectroscopic unit 112 obtains the spectroscopic spectrum of the light received by the light receiving unit 102 and transmitted via the optical fiber, and outputs a signal indicating the intensity of each wavelength component contained in the light. A general spectrometer or a spectroscopic sensor can be used as the spectroscopic unit 112. For example, a spectroscopic unit composed of a combination of multiple sensors having sensitivity only at a specific wavelength can be used, or a sensor capable of detecting a wide band of wavelengths can be used.

[0113] The driving signal generating unit 113 is constituted by, for example, a pulse generator, and generates a driving signal to be applied to one or more piezoelectric vibrators constituting the ultrasonic transmitting and receiving unit 103 .

[0114] The ultrasonic signal processing unit 114 is composed of, for example, an amplifier and an A / D converter, and generates a digital ultrasonic reception signal by performing signal processing such as amplification and A / D conversion on the ultrasonic reception signal transmitted from the ultrasonic transmission and reception unit 103 .

[0115] The operation input unit 115 is configured using input devices such as operation buttons, an operation lever, a keyboard, a mouse, and a touch panel, and inputs a signal corresponding to an operation performed from the outside to the control unit 130 .

[0116] The display unit 116 is, for example, a liquid crystal display or an organic EL display, and displays information such as an ultrasonic image based on ultrasonic reception signals and measurement results of biomarker concentrations under the control of the control unit 130 .

[0117] The storage unit 120 is, for example, a semiconductor memory such as a ROM or a RAM or a computer-readable storage medium such as a hard disk, and includes a program storage unit 121 , a parameter storage unit 122 , and a measurement result storage unit 123 .

[0118] The program storage unit 121 stores application programs for executing various functions in addition to the operating system program and the driver program for operating the control unit 130. Specifically, the program storage unit 121 stores a measurement program for causing the control unit 130 to execute an operation of measuring the biomarker concentration based on the spectral spectrum obtained by the spectroscopic unit 112, a determination program for causing the control unit 130 to execute an operation of determining the malignancy of an endometrial ovarian cyst based on the biomarker concentration, and the like.

[0119] The parameter storage unit 122 stores various parameters used in the execution of the program stored in the program storage unit 121. For example, the parameter storage unit 122 stores the parameters of a formula used in the execution of the biomarker concentration measurement program. The formula is a formula that represents the relationship between the absorbance at a specific plurality of wavelengths and the biomarker concentration in the body, and is represented by the above formula (2). The parameter storage unit 122 stores, for example, the coefficient a constituting the formula (2): n and a constant b. In addition, the parameter storage unit 122 stores a cutoff value of hemoglobin concentration used in the determination program of the malignancy of endometrial ovarian cyst.

[0120] The measurement result storage unit 123 stores measurement results such as the measurement value of the biomarker (hemoglobin) concentration and the malignancy of the endometrial ovarian cyst.

[0121] The control unit 130 is constituted by, for example, a CPU (Central Processing Unit), and controls the various units of the hemoglobin concentration measurement system 10 by reading various programs stored in the program storage unit 121, and performs various calculation processes for measuring the biomarker concentration and determining the malignancy of the endometrial ovarian cyst based on the measurement result. Specifically, the functional units implemented by the control unit 130 include: a light source control unit 131, an absorbance acquisition unit 132, a concentration calculation unit 133, a determination unit 134, a scanning control unit 135, an image processing unit 136, and a display control unit 137.

[0122] The light source control unit 131 controls the on / off of the light source 111 and the irradiation time, irradiation intensity, etc. according to the signal input from the operation input unit 115. In addition, in the present embodiment, since it is sufficient to obtain the spectral spectrum of the reflected light or the transmitted light from the biological tissue, even if the irradiation time of the light in one measurement is relatively long, milliseconds are sufficient.

[0123] The absorbance acquisition unit 132 acquires the measured value of the absorbance at the wavelength based on the signal indicating the intensity of the wavelength component output from the spectroscopic unit 112. The absorbance can be calculated based on the Lambert-Beer law using the above formula (1).

[0124] The concentration calculation unit 133 substitutes the measured value of the absorbance acquired by the absorbance acquisition unit 132 into the parameter stored in the parameter storage unit 122 (for example, the coefficient a in the above formula (2)). n In the formula composed of and constant b), the concentration of the biomarker is calculated.

[0125] The determination unit 134 determines the malignancy of the endometrial ovarian cyst by comparing the concentration of the biomarker calculated by the concentration calculation unit 133 with the cutoff value stored in the parameter storage unit 122. For example, the determination unit can determine that the cyst is undergoing canceration with a probability of 85.7% when the hemoglobin concentration in the cyst fluid is 0.0 to 2.0 g / dL.

[0126] The scanning control unit 135 controls the generation timing (delay pattern of the signal) of the driving signal generating unit 113, thereby scanning the subject using the ultrasonic waves transmitted from the ultrasonic wave transmitting and receiving unit 103. The scanning pattern based on the ultrasonic wave is not particularly limited, and radial scanning, sector scanning, etc. can be appropriately set according to the shape of the probe, the scanning target part, etc.

[0127] The image processing unit 136 generates an ultrasonic image based on the digital ultrasonic reception signal generated by the ultrasonic signal processing unit 114 .

[0128] The display control unit 137 controls the display unit 116 so that predetermined information such as information inputted via the operation input unit 115 and information processed in the control unit 130 is displayed in a predetermined form. For example, the display control unit 137 can display the direction of light emitted from the irradiation unit 101 of the probe 100 on the ultrasonic image by overlapping the ultrasonic image generated by the image processing unit 136 on the display unit 116 through animation. Thus, the user operating the hemoglobin concentration measurement system 10 can confirm the position of the measurement object (e.g., ovarian cyst) of the biomarker concentration and reliably irradiate the measurement object with light. In addition, the display control unit 137 can also control in a manner that the information indicating the biomarker concentration calculated by the concentration calculation unit 133 is overlapped and displayed in the measurement object area of ​​the biomarker concentration in the ultrasonic image. As a specific example, a grid of color and brightness corresponding to the value of the biomarker concentration can also be overlapped with the area of ​​the ovarian cyst in the ultrasonic image. In addition, the display control unit 137 can also display an alarm corresponding to the determination result based on the determination result of the determination unit 134 on the display unit 116.

[0129] In addition, the main body 110 may be composed of one device, or may be composed of a plurality of devices connected via a communication cable or a communication network.

[0130] In the embodiment, the irradiating unit 101 and the light receiving unit 102 are provided on the probe 100 side, and the light source 111 and the spectroscopic unit 112 are provided on the main body 110 side. However, the light source 111 or the spectroscopic unit 112 or both may be provided on the probe 100 side.

[0131] In addition, in this embodiment, the irradiation unit 101 and the light receiving unit 102 are provided in the same probe, but they may be provided in different probes. For example, the light receiving unit 102 is provided on the transvaginal probe, and the light transmitted through the ovarian cyst can be received in the vagina by irradiating light from the surface of the abdomen. Alternatively, the irradiation unit 101 may be provided on the transvaginal probe, and the light transmitted through the ovarian cyst can be received on the surface of the abdomen by irradiating light from the vagina.

[0132] In addition, in the present embodiment, the hemoglobin concentration measurement system is combined with the ultrasonic image generation unit, but it can also be combined with a medical image generation unit other than ultrasonic images such as MRI. In this case, the hemoglobin concentration measurement result based on the system of the present embodiment can also be superimposed on the medical image generated by the medical image generation unit.

[0133] In addition, in the present embodiment, the malignancy of the endometrial ovarian cyst is determined by comparing the hemoglobin concentration obtained as a result of the measurement with a pre-set cutoff value, but further, the malignancy can also be determined by combining with data such as the age of the subject (patient) and the size of the cyst. In addition, the size of the cyst can be measured based on an ultrasonic image or an MRI image. For example, in epidemiology, it is known that when the patient is over 44 years old or the maximum diameter of the cyst is over 84 mm, the possibility of endometrial ovarian cysts becoming cancerous is high, so the cutoff value can also be adjusted according to the patient's age and the size of the cyst.

[0134] As described above, according to the present embodiment, by substituting the measured values ​​of absorbance at specific wavelengths obtained by irradiating light to biological tissue into a pre-acquired formula representing the relationship between absorbance at specific wavelengths and the concentration of the biomarker, the concentration of the biomarker is calculated, so that the concentration of the biomarker in the liquid retained in the biological tissue can be quantitatively, non-invasively and with high precision on the spot. In addition, since the above-mentioned formula is obtained in advance, the measurement can be performed quickly and in real time. Furthermore, for the subject, since the concentration of the biomarker can be measured in a non-constrained manner, painlessly or with reduced pain, and without blood test, it is also possible to perform an examination with less physical burden.

[0135] In addition, according to the present embodiment, when measuring the hemoglobin concentration in the cyst fluid, since two or more wavelengths are selected from 12 wavelengths of 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm, it is possible to obtain an optical signal that reflects the hemoglobin concentration with high accuracy and is not easily affected by factors such as the thickness, composition, water content, and optical path length of biological tissues such as interstitial cells or visceral fat present around the cyst fluid. Therefore, the hemoglobin concentration can be measured with high accuracy regardless of the difference in the thickness and composition of interstitial cells. Furthermore, since the above 12 wavelengths are in the wavelength range from visible light to near-infrared light, a highly safe inspection can be performed.

[0136] In addition, according to this embodiment, since the hemoglobin concentration can be measured using two or more wavelengths selected from the above 12 wavelengths, a light source can be formed by combining a plurality of LEDs having different peak wavelengths. In other words, the degree of freedom in designing the optical system can be increased.

[0137] Here, in the present embodiment, a multiple regression equation is constructed based on the measurement using a simulated cyst. Therefore, when the hemoglobin concentration in the cyst fluid is measured in vivo, the influence of tissues such as interstitial cells or visceral fat can be reduced by using the multiple regression equation. However, the body temperature of the body and the subject (patient) are in a different environment from that in the laboratory. Moreover, it is difficult to reproduce the environment in the body of each subject in the laboratory and to construct a multiple regression equation based on the measurement using a simulated cyst in such an environment. In this regard, since visible light is less susceptible to the influence of temperature, the influence of different environments such as temperature on the measured values ​​can be reduced by using visible light and near-infrared light or only visible light in the measurement using a simulated cyst and the measurement in the body of the subject. Thus, based on the multiple regression equation obtained by the measurement using a simulated cyst, the hemoglobin concentration in the cyst fluid can be stably measured in vivo.

[0138] In addition, according to this embodiment, since the hemoglobin concentration can be measured using absorbance at at least two wavelengths, the calculation load is small. Therefore, even when using a device with the same specifications as a personal computer for daily necessities, the measurement result can be obtained at a high speed. Therefore, the system can be miniaturized and the manufacturing cost and running cost can be reduced.

[0139] In addition, according to the present embodiment, since the hemoglobin concentration in the cyst fluid retained in the ovarian cyst can be measured non-invasively and with high accuracy on the spot, the malignancy can be determined easily, non-invasively, frequently and with high accuracy by referring to the classification or cut-off value of the malignancy of the endometrial ovarian cyst that is previously associated with the hemoglobin concentration. Therefore, for patients diagnosed with endometrial ovarian cysts, unnecessary surgeries such as ovarian removal are reduced in consideration of the possibility that the ovarian cyst will become cancerous in the future, even though the ovarian cyst is not currently cancerous, and the physical and economic burdens of the patients can be reduced.

[0140] In addition, according to this embodiment, when determining the malignancy of endometrial ovarian cysts, there is no need to consider the side effects of contrast agents and X-ray radiation. In addition, in this embodiment, since the measurement time is in the millisecond level, even when a light source containing ultraviolet rays is used, the impact on the organism is small. Therefore, the patient's physical burden is small, and frequent examinations can be performed.

[0141] In addition, according to this embodiment, the malignancy of endometrial ovarian cysts can be determined simply and quickly without using large equipment such as MRI. Therefore, it can be applied to the diagnosis or regular diagnosis in small-scale clinics. In particular, by using Figure 5The hemoglobin concentration measurement system described above can automatically perform everything from hemoglobin concentration measurement to malignancy determination, thereby increasing the possibility of changing treatment plans, such as administering medication in accordance with process observation or determination results, and performing appropriate surgical treatment at a necessary stage.

[0142] Furthermore, the method for determining the malignancy of an endometrial ovarian cyst described in this embodiment is not a method for achieving a definitive diagnosis of whether an endometrial ovarian cyst is becoming cancerous. The definitive diagnosis of whether an endometrial ovarian cyst is becoming cancerous is determined based on pathological histology.

[0143] (Example)

[0144] Based on the spectral spectrum of transmitted light of a simulated biological sample simulating an ovarian cyst (hereinafter referred to as a simulated cyst), a formula for calculating hemoglobin concentration was prepared, and an experiment was conducted to verify the accuracy of hemoglobin concentration calculated using the formula.

[0145] Example 1-1

[0146] (1) Preparation of samples (simulated cysts)

[0147] The hemoglobin aqueous solution was prepared by dissolving hemoglobin powder (manufactured by SYSMEX Co., Ltd., hemolysed hemoglobin) in pure water. The hemoglobin concentration was 6 kinds of 0.0 g / dL (pure water only), 0.5 g / dL, 1.0 g / dL, 2.0 g / dL, 3.0 g / dL, and 4.0 g / dL. In addition, these concentrations are the concentration ranges around the hemoglobin concentration of 2.0 g / dL, which is the cutoff value of the malignancy of endometrial ovarian cysts. The hemoglobin concentration was measured using a blood analyzer (manufactured by SYSMEX Co., Ltd., model: XN-330).

[0148] Into a disposable polystyrene reaction cup (manufactured by Biorad, with an internal dimension of 10mm×10mm×45mm) and two sizes of glass reaction cups (manufactured by Tokyo Glass Instrument Co., Ltd., with an internal dimension of 10mm×10mm×45mm and 20mm×10mm×45mm), 4 mL of the hemoglobin aqueous solution of each concentration was injected and sealed with a sealing film. Furthermore, the container filled with the hemoglobin aqueous solution was turned sideways and wrapped with pork to make a simulated cyst. The thickness of the pork in the part in contact with the optical fiber (described later) was 5 mm and 10 mm. As samples, a total of 36 simulated cysts with two types of pork thickness and three types of containers were prepared for the above-mentioned six hemoglobin concentrations.

[0149] (2) Irradiating simulated cysts with light and obtaining absorbance

[0150] Two optical fibers for near infrared rays (manufactured by Hamamatsu Photonics Co., Ltd., Model: A7969-08AS and A9763-01) were arranged in parallel with their top surfaces being in the same plane and with a center-to-center distance of 18 mm, and fixed using an optical fiber holder (manufactured by Thorlabs, ADASMAB2). Then, the positions of the optical fiber holder and the sample stage were adjusted so that the top surfaces of the two optical fibers were in contact with the simulated cyst placed on the sample stage, and the optical fiber holder and the sample stage were fixed to the optical test stage so that the optical axis would not deviate during the measurement, thereby setting the optical system.

[0151] In addition, a halogen lamp (manufactured by Hamamatsu Photonics Co., Ltd., High Power UV / Vis, Model: L10290) was connected to the rear end of one optical fiber (A9763-01) as a light source, and a spectrometer (manufactured by Hamamatsu Photonics Co., Ltd., Model: C9405CB) was connected to the rear end of the other optical fiber (A7969-08AS). Furthermore, a black polypropylene plate was processed to make a dark box to cover the measurement optical system so that no extra light such as sunlight or lighting would enter from the outside.

[0152] Figure 6 : is a top view schematically showing the above-mentioned measuring optical system. By making the top surfaces of the two optical fibers 201 and 202 contact with the simulated cyst 200, the light emitted from the top surface of the optical fiber 201 on one side is incident on the inside of the simulated cyst 200. The light is reflected in the simulated cyst 200, and a part of the reflected light is incident on the top surface of the optical fiber 202 on the other side. The light incident on the optical fiber 202 contains information related to the liquid contained in the container 203 in the simulated cyst 200. In addition, in Figure 6 In the figure, the dark box 204 is indicated by a single dot-dash line. In addition, when actually measuring, the simulated cyst was covered with a food-use plastic wrap to prevent dirt.

[0153] First, after the power of the light source and the spectrometer is turned on for more than 30 minutes, no objects are placed on the sample table, and the spectroscopic spectrum is obtained in a state where the dark box is covered, and the light intensity I0 at each wavelength is measured. Next, the simulated cyst is placed on the sample table to obtain the spectroscopic spectrum, and the light intensity I1 at each wavelength is measured. The measurement point (wavelength) is a wavelength of 1025 points detectable in 434nm~1144nm according to the specifications of the spectrometer. Then, according to the Lambert-Beer law, the absorbance at each wavelength is calculated from the light intensity I0 and the light intensity I1. This measurement was performed 4 times for each of the simulated cysts with 6 concentrations, 2 thicknesses, and 3 containers, for a total of 144 such measurements.

[0154] Figure 7This is a graph showing the second derivative of the spectral spectrum obtained in each measurement. As the second derivative, the Savitzky-Golay method is used. Here, the significant difference of the original spectrum in the second derivative of the spectral spectrum appears as a downward peak. Figure 7 As shown, in this embodiment, peaks that are obviously not noise are observed at 12 wavelengths of 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm. These peaks are considered to be peaks that characterize the hemoglobin concentration in the simulated cyst.

[0155] (3) Create and verify regression equations

[0156] Among the 144 measurement results obtained by the above measurement (each of which is the absorbance at a wavelength of 1025 points), 30 measurement results were randomly extracted and removed, and the remaining 114 measurement results were used to perform regression analysis, thereby obtaining a regression formula. As a regression analysis, the absorbance at all wavelengths of 1025 points was used as an explanatory variable, and the hemoglobin concentration obtained by actual measurement using a blood analyzer was used as a response variable, and PLS analysis, which is a type of multivariate analysis, was performed.

[0157] The hemoglobin concentration was calculated by substituting the removed 30 measurement results (same as above) into the obtained regression equation, and then the correlation between the hemoglobin concentration calculated by substituting into the regression equation and the hemoglobin concentration obtained by directly measuring the hemoglobin aqueous solution with a blood analyzer was obtained.

[0158] Figure 8 This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (hereinafter referred to as the directly measured concentration) and the measured hemoglobin concentration obtained by the regression equation (hereinafter referred to as the calculated concentration). The correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the regression equation is R=0.91, and a high correlation is confirmed between the two. It can be seen that the hemoglobin concentration in the aqueous solution inside the simulated cyst wrapped in meat can be measured with high accuracy without removing it from the meat. In addition, it can be seen that even for various simulated cysts with different meat thickness and reaction cup sizes, a unified regression equation can be made to calculate the hemoglobin concentration.

[0159] Here, patients suffering from endometrial ovarian cysts have individual differences in cell thickness, density of visceral fat or muscle tissue, size of tumor, etc. In the measurement method of this embodiment, for patients with such various conditions, a unified regression formula can be applied to measure the hemoglobin concentration in the cystic fluid in the ovarian cyst, which can be said to be a highly versatile measurement method.

[0160] Example 1-2

[0161] Using the measurement results obtained by the experiment in the above-mentioned Example 1-1, regression analysis was performed in the same manner as in Example 1-1 to obtain a regression equation, and the hemoglobin concentration was calculated using the regression equation. However, as an explanatory variable, the second derivative of the spectral spectrum (see Figure 7 ) in which significant downward peaks were observed in the absorbance at 12 wavelengths of 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm.

[0162] Fig. 9 This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (directly measured concentration) and the measured hemoglobin concentration (calculated concentration) calculated by a regression equation using absorbance at 12 wavelengths. The correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the regression equation is R = 0.88. As such, even when the explanatory variable is limited to the absorbance at the above 12 wavelengths, a good correlation is confirmed between the direct measured concentration of hemoglobin based on the blood analyzer and the calculated concentration of hemoglobin based on the regression equation.

[0163] Examples 1-3

[0164] Using the measurement results obtained by the experiment in the above-mentioned Example 1-1, regression analysis was performed in the same manner as in Example 1-1 to obtain a regression equation, and the hemoglobin concentration was calculated using the regression equation. However, as an explanatory variable, only the second derivative of the spectral spectrum (see Figure 7 ) The absorbance at two wavelengths, 900 nm and 968 nm, was observed among the 12 wavelengths where significant downward peaks were observed.

[0165] Fig.10 This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (directly measured concentration) and the measured hemoglobin concentration calculated by a regression equation using absorbance at two wavelengths (calculated concentration). Even when the explanatory variable is limited to the absorbance at the above two wavelengths, the correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the regression equation is R=0.89, and a good correlation is confirmed between the two.

[0166] Examples 1-4

[0167] Using the measurement results obtained by the experiment in the above-mentioned Example 1-1, regression analysis was performed in the same manner as in Example 1-1 to obtain a regression equation, and the hemoglobin concentration was calculated using the regression equation. However, as an explanatory variable, the second derivative of the spectral spectrum (see Figure 7 ) is the absorbance at any two or more wavelengths among the 12 wavelengths of 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm, in which a significant downward peak is observed.

[0168] Fig.11 This is a table showing the correlation coefficient between the wavelength of absorbance used for the preparation of the regression equation, the calculated concentration of hemoglobin based on the regression equation, and the directly measured concentration of hemoglobin based on the blood analyzer. Fig.11 As shown, the correlation coefficient is R=0.83 or more in any combination of wavelengths, and a good correlation is observed between the two. It can be seen that by using the absorbance at any two or more wavelengths among the above 12 wavelengths, a regression equation that can calculate the hemoglobin concentration with high accuracy can be created.

[0169] In addition, since visible light does not penetrate living organisms, near-infrared light has been used in all spectroscopic measurements of living organisms. Fig.11 As shown, it can be seen that even when only visible light or visible light and near-infrared light are used, accuracy equivalent to or higher than that of the case of using only near-infrared light can be obtained.

[0170] Example 2-1

[0171] (1) Preparation of samples (simulated cysts)

[0172] Samples (cyst fluid) provided by 9 patients who underwent ovarian removal surgery were prepared. The hemoglobin concentration of these samples was measured using a blood analyzer (manufactured by SYSMEX Co., Ltd., model: XN-330), and the range was 0.1 g / dL to 3.8 g / dL. In addition, a blank with a hemoglobin concentration of 0.0 g / dL was prepared by dissolving human albumin (manufactured by Nacalai Tesque Co., Ltd.) in phosphate buffered saline (albumin concentration 5.0 g / dL), and a total of 10 samples were prepared.

[0173] As in Example 1-1, 4 mL of each of these samples was injected into a disposable polystyrene reaction cup (manufactured by Biorad, with an internal size of 10 mm × 10 mm × 45 mm), sealed with a sealing film, and wrapped with pork to make a simulated cyst. The thickness of the pork in the part in contact with the optical fiber was 5 mm and 10 mm. As samples, a total of 20 simulated cysts with two different thicknesses of pork were prepared for the above 10 samples.

[0174] (2) Irradiating simulated cysts with light and obtaining absorbance

[0175] The measurement optical system was set up in the same manner as in Example 1-1, and the experiment was performed twice for each sample, for a total of 40 times to obtain the spectral spectrum of light transmitted through the simulated cyst and calculate the absorbance.

[0176] Fig.12 is a graph showing the second derivative of the spectral spectrum obtained in each measurement. Fig.12 As shown, in this embodiment, as in Example 1-1, characteristic peaks are observed at 12 wavelengths of 580nm, 590nm, 640nm, 680nm, 762nm, 876nm, 900nm, 932nm, 958nm, 968nm, 978nm, and 1095nm. Considering Examples 1-1 and 2-1, it is considered that these peaks are not dependent on the source of the measurement object, but are peaks unique to chemical species such as hemoglobin.

[0177] (3) Create and verify regression equations

[0178] Among the 40 measurement results obtained by the above measurement (each of which is the absorbance at a wavelength of 1025 points), 10 measurement results were randomly extracted and removed, and the remaining 30 measurement results were used for regression analysis to obtain a regression formula. As a regression analysis, similar to Example 1-1, PLS analysis was performed using the absorbance at all wavelengths of 1025 points as an explanatory variable and the hemoglobin concentration measured by a blood analyzer as a response variable.

[0179] The hemoglobin concentration was calculated by substituting the 10 measurement results (same as above) removed into the obtained regression equation, and then the correlation between the hemoglobin concentration calculated by substituting into the regression equation and the hemoglobin concentration obtained by directly measuring the sample with a blood analyzer was obtained.

[0180] Fig.13This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (directly measured concentration) and the measured hemoglobin concentration calculated by a regression equation (calculated concentration). The correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the regression equation is R=0.97, and a high correlation is confirmed between the two.

[0181] As described above, according to Example 2-1, it is possible to measure the hemoglobin concentration of not only the hemoglobin aqueous solution but also the clinical sample provided by the patient without taking it out from the simulated cyst, that is, non-invasively and with high accuracy.

[0182] Example 2-2

[0183] From the measurement results obtained in the experiment of Example 2-1 above, after removing 10 measurement results, a calibration curve was prepared based on the absorbance at two wavelengths of 900 nm and 968 nm. Then, the hemoglobin concentration was calculated by applying the 10 measurement results removed to the calibration curve. Fig.14 This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (directly measured concentration) and the measured hemoglobin concentration calculated by the calibration curve obtained by PLS analysis (calculated concentration). The correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the calibration curve is R = 0.92, and a high correlation is confirmed between the two.

[0184] Example 3

[0185] (1) Preparation of samples (simulated cysts)

[0186] As in Example 1-1, 6 kinds of hemoglobin aqueous solutions adjusted to 0.0 g / dL (pure water only), 0.5 g / dL, 1.0 g / dL, 2.0 g / dL, 3.0 g / dL, and 4.0 g / dL were sealed in a polystyrene reaction cup (manufactured by Biorad, inner dimensions 10 mm×10 mm×45 mm) and rolled with pork to prepare simulated cysts. By setting the thickness of the meat to two kinds, 5 mm and 10 mm, a total of 12 kinds of simulated cysts were prepared.

[0187] (2) Irradiating simulated cysts with light and obtaining absorbance

[0188] Using a body cavity probe (transvaginal probe) used in ultrasonic diagnosis, an experimental probe was prepared in which an optical fiber was buried at the tip of the probe. Fig.152 is a top view schematically showing the front end (head) of the probe used in Example 3. The width of the head of the probe 210 is 21.8 mm, and an ultrasonic wave transmitting and receiving unit 211 is provided in the center of the head. For such a body cavity probe, the optical fiber 212 connected to the light source and the optical fiber 213 connected to the spectrometer are installed in such a way that the top end surface of each optical fiber 212, 213 is flush with the surface of the head. The center-to-center distance of the optical fibers 212, 213 is 18 mm.

[0189] For such an experimental probe, ultrasound gel (manufactured by JEX Co., Ltd.) was applied to the tip of the probe and covered with a probe cap (manufactured by Fuji Latex Co., Ltd.) in the same manner as in the usual procedure for ultrasound diagnosis. In addition, the usual procedure was followed to verify whether light detection was possible even if there was light attenuation caused by ultrasound gel and the probe cap.

[0190] The experimental probe was fixed to the optical table, and the light intensity I0 measured without the simulated cyst on the sample table and the light intensity I1 measured with the simulated cyst on the sample table were obtained in the same manner as in Example 1-1. Then, according to the Lambert-Beer law, the absorbance at each wavelength was calculated from the light intensity I0 and the light intensity I1. This measurement was performed 3 times for each of the 6 concentrations and 2 thicknesses of the simulated cysts, for a total of 36 times.

[0191] (3) Create and verify regression equations

[0192] Among the 36 measurement results obtained by the above measurement (each of which is the absorbance at a wavelength of 1025 points), 9 measurement results were randomly extracted and removed, and the remaining 27 measurement results were used for regression analysis to obtain a regression formula. As a regression analysis, similar to Example 1-1, PLS analysis was performed using the absorbance at all wavelengths of 1025 points as an explanatory variable and the hemoglobin concentration obtained by actual measurement using a blood analyzer as a response variable.

[0193] The hemoglobin concentration was calculated by substituting the measurement results of the 9 removed times (same as above) into the obtained regression equation, and then the correlation between the hemoglobin concentration calculated by substituting into the regression equation and the hemoglobin concentration obtained by directly measuring the hemoglobin aqueous solution with a blood analyzer was obtained. Fig.16 This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (directly measured concentration) and the measured hemoglobin concentration calculated by a regression equation (calculated concentration). The correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the regression equation is R=0.89, and a good correlation is confirmed between the two.

[0194] As described above, it is known that even when the measurement optical system is not constituted by a special optical fiber holder for optical experiments, the hemoglobin concentration of the fluid in the simulated cyst can be measured non-invasively and with high accuracy by mounting an optical system such as an optical fiber on the body cavity probe. In addition, it was confirmed that even when using ultrasound gel and a probe cover used in ultrasound diagnosis, a sufficient amount of light can be detected for the measurement of hemoglobin concentration.

[0195] (Second embodiment)

[0196] Fig.17 It is a side view schematically showing a transvaginal probe according to a second embodiment of the present invention. Fig.18 yes Fig.17 A top view of a transvaginal probe is shown. Fig.19 yes Fig.17 Magnified view in the X direction. Fig. 20 This is a schematic diagram for explaining the relationship between an ultrasonic image and the irradiation direction of light.

[0197] Figure 17 to Figure 19 The transvaginal probe 300 shown is a probe mainly used to measure the hemoglobin concentration in the cyst fluid retained in the endometrial ovarian cyst, and has: an ultrasonic transmission and reception function of transmitting ultrasonic waves to the biological tissue of the subject (patient) and receiving ultrasonic echoes reflected from the biological tissue; a function of irradiating light to the biological tissue; and a light receiving function of receiving reflected light reflected from the biological tissue or transmitted light passing through the biological tissue. Such a transvaginal probe 300 is, for example, Figure 5 The main body 110 of the hemoglobin concentration measurement system 10 shown is connected and used, and can constitute a part of the hemoglobin concentration measurement system.

[0198] Specifically, the transvaginal probe 300 includes a transvaginal ultrasonic probe 310 and an optical transmission and reception attachment 320 that can be attached to and detached from the ultrasonic probe 310 .

[0199] An ultrasonic transmitter-receiver 312 is provided at the front end of the insertion portion 311 of the ultrasonic probe 310 that is inserted into the vagina. The ultrasonic transmitter-receiver 312 transmits ultrasonic waves to the living tissue and receives ultrasonic echoes reflected from the living tissue. The ultrasonic transmitter-receiver 312 is composed of a plurality of piezoelectric vibrators arranged in a predetermined order. The ultrasonic transmitter-receiver preferably scans the living tissue in a convex shape using the ultrasonic waves transmitted from the front end of the insertion portion 311. The ultrasonic transmitter-receiver 312 generates ultrasonic waves based on a driving electrical signal transmitted from the main body 110 connected to the ultrasonic probe 310 via a cable 313, receives ultrasonic echoes reflected from the living tissue, converts them into electrical signals (ultrasonic reception signals), and transmits them to the main body 110 via the cable 313.

[0200] The attachment 320 includes: a bracket 321 covering the insertion portion 311; an optical fiber 322 for transmitting light connected to the light source 111 of the main body 110; an irradiation unit 323 for irradiating the biological tissue of the subject with light transmitted through the optical fiber 322; a light receiving unit 324 for receiving reflected light reflected from the biological tissue or transmitted light passing through the biological tissue; and an optical fiber 325 for receiving light connected to the spectroscopic unit 112 of the main body 110 and transmitting the light received by the light receiving unit 324 to the spectroscopic unit 112. The irradiation unit 323 and the light receiving unit 324, as well as at least a part of the optical fibers 322 and 325 are mounted on the bracket 321.

[0201] The support 321 is formed of a biocompatible resin material such as polyurethane or polyetheretherketone, polymethyl methacrylate, polyisoprene, etc. The raw material of the support 321 is not limited as long as it is a material showing biocompatibility that ensures the safety of the subject, and the hardness and color of the material are not limited. The support 321 fixes the irradiation part 323 and the light receiving part 324 and a part of the optical fibers 322 and 325 to the insertion part 311, and protects these optical components in a manner that does not directly contact the biological tissue in the vagina. Furthermore, the support 321 holds the irradiation part 323 and the light receiving part 324 in a manner that the end faces of the irradiation part 323 and the light receiving part 324 do not protrude more than the end faces of the ultrasonic transmitting and receiving part 312.

[0202] The irradiation unit 323 is, for example, an irradiation unit having an optical system such as a focusing lens at the end of the optical fiber 322 for transmitting light, and emits light containing specific wavelength components from visible light to near-infrared light transmitted from the light source. The irradiation unit 323 is mounted on the bracket 321 in such a manner that the light can be irradiated to the biological tissue located in a predetermined direction when the transvaginal probe 300 is inserted into the vagina.

[0203] The light receiving unit 324 is a light receiving unit having an optical system such as a focusing lens for focusing light at the end of an optical fiber 325 for receiving light, and receives light containing specific wavelength components from visible light to near-infrared light. The light receiving unit 324 is mounted on the bracket 321 in such a manner that it can receive reflected light of the light emitted from the irradiation unit 323 and reflected by the living tissue located in a predetermined direction or transmitted light that passes through the living tissue when the transvaginal probe 300 is inserted into the vagina.

[0204] The irradiation unit 323 and the light receiving unit 324 are provided at positions that have a predetermined positional relationship with respect to the ultrasonic wave transmitting and receiving unit 312 when the support 321 is covered on the insertion unit 311. Fig. 20As shown, the irradiation unit 323 is arranged in a manner to emit light in a direction parallel to the scanning plane of the ultrasonic wave transmitted by the ultrasonic wave transmitting and receiving unit 312. In addition, the light receiving unit 324 is arranged in a manner to receive reflected light or transmitted light emitted from the irradiation unit 323 and reflected by the biological tissue or transmitted through the biological tissue and propagated in a direction parallel to the above-mentioned scanning plane. Thus, it is possible to irradiate the biological tissue on the scanning plane displayed as an ultrasonic image with light and receive the reflected light or transmitted light thereof. Here, in this specification, parallel to the scanning plane of the ultrasonic wave means that in addition to the state that the emission direction of light (in other words, the direction of the optical axis of the optical system provided in the irradiation unit 323) or the propagation direction of light (in other words, the direction of the optical axis of the optical system provided in the light receiving unit 324) is completely parallel to the scanning plane, it also includes a range in which the scanning plane in the body of the subject is substantially parallel to the emission direction or the propagation direction to the extent that it does not intersect (for example, within an angle of ±5° relative to the scanning plane).

[0205] In addition, when the scanning method of the ultrasound wave by the ultrasound transmitting and receiving unit 312 is a convex type, the irradiation unit 323 may be arranged so as to emit light in a direction parallel to the transmission direction of the ultrasound wave at the center of the convex scanning surface. Thus, the living body tissue located at the center in the scanning direction of the ultrasound image can be irradiated with light.

[0206] like Fig.19 As shown, the irradiating section 323 and the light receiving section 324 are preferably arranged in a manner that they are located on opposite sides of each other with the ultrasonic transmitting and receiving section 312 therebetween. In addition, the irradiating section 323 and the light receiving section 324 are more preferably arranged in a manner that a line connecting the end face of the irradiating section 323 and the end face of the light receiving section 324 is orthogonal to the scanning direction of the ultrasonic wave transmitted from the ultrasonic transmitting and receiving section 312. Furthermore, the irradiating section 323 and the light receiving section 324 are preferably arranged in a manner that a line connecting the end face of the irradiating section 323 and the end face of the light receiving section 324 passes through approximately the center of the scanning line of the ultrasonic wave. By arranging the irradiating section 323 and the light receiving section 324 in this way, light can be emitted in a direction that is approximately parallel to the scanning plane of the ultrasonic wave and is approximately the center of the scanning range of the ultrasonic wave. Thus, as Fig. 20 As shown, the ovarian cyst captured by the ultrasonic image can be reliably irradiated with light, and an optical signal containing information related to the cystic fluid retained in the ovarian cyst can be obtained.

[0207] Here, from the viewpoint of irradiating light to the living body tissue captured by the ultrasonic image and receiving the reflected light or transmitted light, it is preferable to arrange the irradiation unit 323 and the light receiving unit 324 as close as possible to the ultrasonic transmission and reception unit 312. On the other hand, if the interval between the irradiation unit 323 and the light receiving unit 324 is too close, the scattered light generated by the light emitted from the irradiation unit 323 being scattered into the tissue in the living body directly enters the light receiving unit 324, and the SN ratio of the optical signal received by the light receiving unit 324 may be reduced. In this regard, Fig.19 As shown, by separating the ultrasonic transmitting and receiving unit 312 between the irradiating unit 323 and the light receiving unit 324, the irradiating unit 323 and the light receiving unit 324 can be brought close to the ultrasonic transmitting and receiving unit 312 and the interval between the irradiating unit 323 and the light receiving unit 324 can be opened, thereby suppressing the reduction of the SN ratio in the optical signal received by the light receiving unit 324.

[0208] The center-to-center distance between the irradiation section 323 and the light receiving section 324 is preferably approximately not less than 10 mm and not more than 31 mm. In order to suppress the scattered light of the light emitted from the irradiation section 323 from being directly incident on the light receiving section 324, the center-to-center distance is preferably set to be not less than 10 mm. Within a certain range, the longer the center-to-center distance is extended, the more likely it is to reduce the noise caused by scattered light. On the other hand, if the center-to-center distance is extended, the size of the front end of the transvaginal probe 300 becomes larger, making it difficult to use on the subject, so it is preferred to set the center-to-center distance to be not more than 31 mm to compactly suppress the external dimensions. As shown in the present embodiment, when using the accessory 320, considering the size of the transvaginal probe 300, it is preferred to set the center-to-center distance to be not less than 20 mm and not more than 31 mm.

[0209] As described above, according to the second embodiment of the present invention, by using a transvaginal probe in which an ultrasonic transmitting and receiving unit, a light irradiating unit, and a light receiving unit are arranged in a predetermined positional relationship, it is possible to grasp the emission direction of light relative to an ultrasonic image, so that the user can reliably irradiate light in the direction where the ovarian cyst exists while observing the ultrasonic image. Therefore, based on the reflected light of the irradiated light, the hemoglobin concentration in the cystic fluid held in the ovarian cyst can be measured non-invasively and stably at the site.

[0210] According to the second embodiment of the present invention, by attaching the attachment 320 to the general transvaginal ultrasonic probe 310, a probe capable of measuring the hemoglobin concentration in the cyst fluid while referring to an ultrasonic image can be realized inexpensively and simply.

[0211] Example 4

[0212] (1) Preparation of samples (simulated cysts)

[0213] As in Example 1-1, six kinds of hemoglobin aqueous solutions adjusted to 0.0 g / dL (pure water only), 0.5 g / dL, 1.0 g / dL, 2.0 g / dL, 3.0 g / dL, and 4.0 g / dL were prepared and the adjusted hemoglobin aqueous solutions were used as test samples to be sealed in a phantom model described later.

[0214] (2) Irradiating simulated cysts with light and obtaining absorbance

[0215] As described in the second embodiment, for a transvaginal ultrasonic probe (PVU-781VTE) manufactured by Toshiba Medical Systems Co., Ltd. (now Canon Medical Systems Co., Ltd.), a transvaginal probe equipped with an accessory having a light irradiation portion and a light receiving portion is prepared. The ultrasonic probe is connected to an ultrasonic imaging diagnostic device (Xario100s). An optical fiber (model: M29) manufactured by Thorlbas Corporation is used as an optical fiber for transmitting light, and the same optical fiber is used as an optical fiber for receiving light. The center-to-center distance between the end face of the irradiation portion and the end face of the light receiving portion is set to 30 mm. As for the light source (halogen lamp) and the spectrometer, the same equipment as in Example 1-1 is used.

[0216] For such a transvaginal probe, ultrasound gel (manufactured by JEX Co., Ltd.) was applied to the tip of the probe and covered with a probe cap (manufactured by Fuji Latex Co., Ltd.) in the same manner as in the usual procedure for ultrasound diagnosis. In addition, the usual procedure was followed to verify whether light detection was possible even if there was light attenuation due to ultrasound gel and the probe cap.

[0217] A simulation model of female genitals with an ovarian part simulating an endometrial ovarian cyst was prepared, and a sample to be tested was sealed in it. An enlarged ovarian part was provided in the simulation model, and a liquid was sealed inside the ovarian part, so that ultrasonic images and optical tests could be obtained at the same time. For such a simulation model, the light intensity I0 measured by inserting the above-mentioned transvaginal probe into the vulva and the light intensity I1 measured in the same manner when the sample was injected into the ovarian part were obtained. Then, according to the Lambert-Beer law, the absorbance at each wavelength was calculated from the light intensity I0 and the light intensity I1. Such measurements were performed 6 times for each of the simulated cysts of 6 concentrations and 2 thicknesses, for a total of 72 times. The ovarian part is an ellipsoid with a long axis of about 50 mm and a short axis of about 30 mm. The signal was obtained by irradiating the ovarian part with light while confirming the ultrasonic image.

[0218] (3) Create and verify regression equations

[0219] Among the 72 measurement results obtained by the above measurement (each of which is the absorbance at a wavelength of 1025 points), 15 measurement results were randomly extracted and removed, and the remaining 57 measurement results were used to perform regression analysis, thereby obtaining a regression formula. As a regression analysis, similar to Example 1-1, PLS analysis was performed using the absorbance at all wavelengths of 1025 points as an explanatory variable and the hemoglobin concentration obtained by actual measurement using a blood analyzer as a response variable.

[0220] The hemoglobin concentration was calculated by substituting the 15 measurement results (same as above) removed into the obtained regression equation, and then the correlation between the hemoglobin concentration calculated by substituting into the regression equation and the hemoglobin concentration obtained by directly measuring the hemoglobin aqueous solution with a blood analyzer was obtained. Fig.21 This is a graph showing the correlation between the hemoglobin concentration directly measured by a blood analyzer (directly measured concentration) and the measured hemoglobin concentration calculated by a regression equation (calculated concentration). The correlation coefficient between the direct measured concentration based on the blood analyzer and the calculated concentration based on the regression equation is R=0.97, and a very good correlation is confirmed between the two.

[0221] Here, in Example 1-1 analyzed using the above-mentioned 1025 wavelength, the center-to-center distance between the end face of the irradiation part and the end face of the light receiving part is 18 mm, and the correlation coefficient R is 0.91. In contrast, it is considered that in Example 4, by extending the center-to-center distance, the noise scattered on the surface of the irradiation part is suppressed from directly entering the light receiving part, so the correlation coefficient is improved.

[0222] The present invention is not limited to the first and second embodiments described above, and can be implemented in various other ways without departing from the scope of the gist of the present invention. For example, several components can be removed from all the components shown in the first and second embodiments, or the components shown in the first and second embodiments can be appropriately combined to form.

[0223] [Explanation of Reference Numerals]

[0224] 10…hemoglobin concentration measuring system, 100…probe, 101, 323…irradiation unit, 102, 324…light receiving unit, 103, 312…ultrasonic transmitting and receiving unit, 110…main body, 111…light source, 112…spectrometer, 113…drive signal generating unit, 114…ultrasonic signal processing unit, 115…operation input unit, 116…display unit, 120…storage unit, 121…program storage unit, 122…parameter storage unit, 123…measurement result storage unit, 130…control unit, 131…light source control unit, 1 32…absorbance acquisition unit, 133…concentration calculation unit, 134…judgment unit, 135…scanning control unit, 136…image processing unit, 137…display control unit, 200…simulated cyst, 201, 202, 212, 213…optical fiber, 203…container, 204…dark box, 210…probe, 211, 312…ultrasonic transmitting and receiving unit, 300…transvaginal probe, 310…ultrasonic probe, 311…insertion unit, 313…cable, 320…accessory, 321…bracket, 322, 325…optical fiber.

Claims

1. A hemoglobin concentration measuring system comprising a transvaginal probe, a display unit, and a concentration calculating unit, The transvaginal probe has: an ultrasonic wave transmitting and receiving unit capable of transmitting ultrasonic waves to the ovarian cyst in the living body tissue and capable of receiving ultrasonic wave echoes reflected from the living body tissue; a light irradiation unit capable of emitting light including specific multiple wavelength components in a wavelength range from visible light to near infrared light in a direction parallel to a scanning plane of the ultrasonic wave transmitted by the ultrasonic wave transmitting and receiving unit; and a light receiving unit capable of receiving reflected light or transmitted light emitted from the light irradiation unit and reflected by or passing through the biological tissue and propagating in a direction parallel to the scanning surface, The display unit is capable of displaying an ultrasonic image including an image of the ovarian cyst based on the ultrasonic echo received by the ultrasonic transmitting and receiving unit. The concentration calculation unit calculates the concentration of hemoglobin in the cyst fluid retained in the ovarian cyst based on the spectral spectrum of the reflected light or the transmitted light received by the light receiving unit, The concentration calculation unit obtains the absorbance measurement values ​​at the specific wavelengths, substitutes the absorbance measurement values ​​into a predetermined formula obtained in advance that represents the relationship between the absorbance at the specific wavelengths and the hemoglobin concentration, and thereby calculates the hemoglobin concentration. The specific plurality of wavelengths at least include wavelength components in the visible light region, The predetermined formula obtained in advance is a multiple regression formula constructed using simulated cysts.

2. The hemoglobin concentration measuring system according to claim 1, The ultrasonic wave transmitting and receiving unit transmits ultrasonic waves in a manner of convexly scanning the living body tissue. The light irradiation unit is provided so as to be able to emit the light in a direction parallel to a transmission direction of ultrasonic waves at the center of the convex scanning surface.

3. The hemoglobin concentration measuring system according to claim 1, The light irradiation unit and the light receiving unit are arranged on opposite sides of each other with the ultrasonic wave transmitting and receiving unit interposed therebetween.

4. The hemoglobin concentration measuring system according to claim 1, The light irradiation section and the light receiving section are arranged so that a line connecting an end surface of the light irradiation section and an end surface of the light receiving section is orthogonal to a scanning direction of the ultrasonic wave transmitted from the ultrasonic wave transmitting and receiving section.

5. The hemoglobin concentration measuring system according to claim 1, The distance between the centers of the end surface of the light irradiation section and the end surface of the light receiving section is not less than 10 mm and not more than 31 mm.

6. The hemoglobin concentration measuring system according to claim 1, The ultrasonic wave transmitting and receiving unit is provided in the ultrasonic wave probe for transvaginal use. The light irradiation unit and the light receiving unit are mounted on a bracket, and the bracket covers the insertion portion of the ultrasonic probe to be inserted into the vagina. The light irradiation unit and the light receiving unit are detachable from the ultrasonic probe together with the holder.

7. The hemoglobin concentration measuring system according to any one of claims 1 to 6, The specific plurality of wavelengths include only wavelengths in the visible light region.

8. The hemoglobin concentration measuring system according to any one of claims 1 to 6, The specific plurality of wavelengths include at least two or more wavelengths selected from 580 nm, 590 nm, 640 nm, 680 nm, and 762 nm.

9. The hemoglobin concentration measuring system according to any one of claims 1 to 6, The specific plurality of wavelengths include two or more wavelengths selected from 580 nm, 590 nm, 640 nm, 680 nm, 762 nm, 876 nm, 900 nm, 932 nm, 958 nm, 968 nm, 978 nm, and 1095 nm.

10. The hemoglobin concentration measuring system according to any one of claims 1 to 6, The prescribed formula is determined by a method comprising the following steps: Step a, irradiating a simulated biological sample formed by covering a transparent container with biological tissue with light in a wavelength range from visible light to near-infrared light, wherein the container contains a liquid with a known hemoglobin concentration; Step b, receiving reflected light reflected by the simulated biological sample or transmitted light passing through the simulated biological sample; Step c, obtaining the spectroscopic spectrum of the reflected light or the transmitted light received in step b; as well as, Step d, based on a plurality of spectral spectra obtained by performing steps a to c on a plurality of the simulated biological samples, obtaining absorbances at a plurality of wavelengths, the plurality of wavelengths being a predetermined plurality of wavelengths including at least wavelengths in the visible light region in the wavelength region of the light irradiated in step a, and finding a relationship between the absorbances at the predetermined plurality of wavelengths and the concentration of hemoglobin based on the plurality of absorbances and the concentration of the liquid of known concentration; The specific wavelengths are the prescribed wavelengths.

11. The hemoglobin concentration measuring system according to any one of claims 1 to 6, The method further includes a determination unit that determines whether the hemoglobin concentration calculated by the concentration calculation unit corresponds to one of the categories of malignancy of the endometrial ovarian cyst that are previously correlated with the hemoglobin concentration.

12. A method for determining hemoglobin concentration, comprising: an ultrasonic image display step of receiving an ultrasonic echo reflected from the living body tissue by ultrasonic waves transmitted transvaginally to the ovarian cyst in the living body tissue, and displaying an ultrasonic image including an image of the ovarian cyst based on the ultrasonic echo; a light irradiation step of emitting light including specific multiple wavelength components in a wavelength range from visible light to near infrared light in a direction parallel to a scanning plane of the ultrasonic wave transmitted in the ultrasonic image displaying step; a light receiving step of receiving reflected light or transmitted light emitted in the light irradiation step and reflected by the biological tissue or passing through the biological tissue and propagating in a direction parallel to the scanning surface; and a concentration calculation step of calculating the concentration of hemoglobin in the cyst fluid retained in the ovarian cyst based on the spectral spectrum of the reflected light or the transmitted light received in the light receiving step; The concentration calculation step obtains measured values ​​of absorbance at the specific multiple wavelengths, substitutes the measured values ​​of absorbance into a predetermined formula obtained in advance that represents the relationship between the absorbance at the specific multiple wavelengths and the concentration of hemoglobin, thereby calculating the concentration of hemoglobin, The specific plurality of wavelengths at least include wavelength components in the visible light region, The predetermined formula obtained in advance is a multiple regression formula constructed using simulated cysts.

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