JPS63252134A - Cancer diagnostic apparatus utilizing fluorescence detection - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to hematoporphyrin derivatives (hereinafter referred to as HPD), etc.
Excitation light is irradiated to predetermined areas such as the trachea and bladder of a living body that have been injected with a fluorescent substance that has a strong affinity for Ili tumors, and the resulting fluorescence is irradiated with excitation light.
This invention relates to a cancer diagnostic device that uses fluorescence detection to diagnose tumors based on intensity.

[Conventional technology]

Conventionally, cancer diagnosis and treatment methods and devices have been proposed that utilize photochemical reactions between laser light and fluorescent substances that have a strong affinity for tumors such as HPD. (JP-A-59-40830, JP-A-59-4
No. 0869, USP No. 4556057).

FIG. 9 is a block diagram showing the basic configuration of a conventional diagnostic device, in which 1 is a tissue surface, 2 is an image guide, and 3.
4.5 is a light guide, 6 is a color camera, 7 is a white light source, 8 is a laser light source, 9 is a spectrometer, 10 is a fluorescence spectrum image, 11 is a high-sensitivity camera, 12 is an analysis circuit, 13.1
4 is a monitor, 15 is a fiber bundle, 17 is an endoscope system, 18
is a photochemical reaction diagnostic treatment system.

In the figure, the configuration of the device is divided into a normal endoscopic diagnosis system 17 and a photochemical reaction diagnosis treatment system 18.

The fiber bundle 15 is built into the endoscope, and the HP
It has been inserted into a site thought to be the lesion of a patient who received intravenous injection of D. The endoscope system 17 includes a white light a7 for illuminating the tissue surface 1, a light guide 3 that guides this light, and a tissue surface 1.
image guide 2 that guides the image to the color camera 6;
It consists of a monitor 13 that displays an image of the tissue surface 1 taken by a color camera 6.

On the other hand, the photochemical reaction diagnosis and treatment system 18 is provided with a laser light source 8 that outputs excitation light (405 nm) and treatment light (630 nm) for diagnosis as pulsed laser light. This light is guided to the affected area by the light guide 4 and irradiated onto the affected area.

Next, to explain the operation, the fluorescence generated by the excitation light is guided to the spectrometer 9 by the light guide 5, and the fluorescence spectrum image 10 obtained by the spectrometer 9 is captured by the high-sensitivity camera 11, and the output video The signal 16 is converted into a figure by the analysis circuit 12 through arithmetic processing, and is displayed on the monitor 1 as a spectrum waveform.
Displayed by 4. The spectral image 10 is set in the 600-700 nm region in order to observe the bimodal spectrum of 630 nm and 690 nm characteristic of HPD fluorescence. Since the endoscopic diagnosis and the photochemical reaction diagnosis treatment are performed in parallel, the white light source 7 and the laser light source 8 irradiate the tissue 1 in a time-sharing manner. In synchronization with the laser beam irradiation, the fluorescence spectrum analysis system from the spectrometer 9 to the monitor 14 also operates intermittently.

With this device, the operator can search for the location of cancer while simultaneously viewing the tissue image on the monitor 13 and the fluorescence spectrum waveform on the monitor 14 during diagnosis. Treatment can be performed immediately by simply switching the button. This treatment is performed by selectively necrotizing only the cancerous area through a photochemical reaction between HPD remaining in the cancerous area and therapeutic light.

Furthermore, when confirming fluorescence at the time of diagnosis, since the spectral waveform unique to fluorescence itself is directly observed, there is no confusion with autofluorescence from normal areas, making it easier to identify cancer, especially early cancer. It can greatly contribute to the diagnosis and treatment of patients.

[Problems to be solved by the invention]

As mentioned above, conventional devices utilize HPD's affinity for tumors to perform diagnosis and treatment. In particular, a method of observing the spectral intensity is used to detect fluorescence from an HPD during diagnosis. That is, in the conventional method, the spectral intensity of the total amount of fluorescent light detected by the light guide 5 in FIG. 9 is displayed. However, problems with this method include the following.

(2) It is not possible to confirm which part of the color image on the monitor 13 is being detected by the light guide 5.

(2) Since the two-dimensional fluorescence intensity distribution within the detection range cannot be observed, the exact location and shape of the cancer cannot be determined.

■Even if the two-dimensional intensity distribution of fluorescence can be observed,
This is caused by fluctuations in laser output and m from the irradiation port at the tip of the endoscope.
It changes greatly depending on the distance to i and the irradiation angle, making it extremely difficult to distinguish between a normal area and a cancerous area.

The above-mentioned problems directly affect the basic functions and performance of cancer diagnostic devices, and improvements have been strongly desired.

By the way, regarding the above-mentioned item (1), a method has been proposed in which the reflected light of the excitation light is used to correct the apparent fluctuation of the spectral intensity (Japanese Patent Application No. 61-90149).

FIG. 10 is a diagram for explaining the principle of such correction, and shows the positional relationship between the irradiation fiber and the detection fiber with respect to the tissue.

In the figure, the irradiation fiber 4 is located at a distance l and an angle θ with respect to the surface of the &II fabric 1 to be irradiated, and from here P(
The intensity Iin of the excitation light incident on the tissue, where the excitation light (each time) is emitted toward the biological MIim surface, is determined by the above-mentioned fluctuation factors P, l, θ, as follows: 1in=lin (P, l, θ) Becomes a function. The amount of fluorescent light IF generated by this excitation light is expressed as follows.

1F=, fin・77F−nk, :P, 1. Constant unrelated to θ ηF: Fluorescence efficiency of HPD n: Concentration of HPD Note that the amount of fluorescence (IF) is not in a strictly proportional relationship with the HPD concentration (n), but the practical value of n (10- '~10-
'no 1/1), a proportional relationship holds approximately.

If the generated fluorescence 1F enters the detection fiber.
, if the fluorescence detection efficiency is ηD, If-IF·ηD mk, fin-ηF-n·ηD. ηD is the relative position (1,
θ) and the effective focusing range S shown in FIG.

The effective focusing range S is expressed as the overlap between the excitation light irradiation range and the detection fiber field of view shown in FIG. 11, and varies due to fluctuations of the irradiation fiber, etc., and is expressed as shown in the following equation.

ηD−ηD (L θ, S) Note that since the directivity of the fluorescent light is isodirectional, it is not included as a function in ηD.

On the other hand, the reflected light 1r entering the detection fiber becomes Ir=,
l1n-R・η'D k+; P, ! ! , constant R independent of θ:
Reflectance η'D: given by detection efficiency of reflected light.

Strictly speaking, the reflectance R is a function of n, but for a practical n where 4 degrees is very small, it can be considered almost constant, and has a value determined by the properties of the tissue, and also depends on ηD and η Regarding the comparison of 'D, the following can be said.

First, the location where both reflected light and fluorescent light are generated is the irradiation position of the excitation light, and the same detection fiber is used, so the geometric conditions are exactly the same. Regarding directivity,
Since the scattered reflected light of the reaction light excluding the surface reflected light is isodirectional like the fluorescent light, if only this light is separated and detected by a polarizing filter as necessary, the directivity conditions will be the same.

Therefore, ηD−η′D is realized. In addition, reflected light (405 nm) and fluorescent light (6
The difference in the focusing range due to the difference in wavelength (30 nm) is slight and can be regarded as a fixed factor, so there is no practical problem.

therefore, Ir-, -1in-R・ηD becomes.

When the detected fluorescent light intensity [ is normalized by the detected reflected light intensity + r, it becomes If/[r=kz H77F-n/R. Note that k2 is (ko/ko) and is a constant unrelated to P and Lθ. Therefore, I f / I r is proportional to the fluorescent efficiency of HPD (ηF) and HPD concentration (n), and inversely proportional to the reflectance of biological tissue, and the fluctuation factors P, e1θ, and S at the time of diagnosis are can be removed. That is, all fluctuations in detected fluorescence intensity due to these factors can be corrected.

In this way, using the reflected light of the excitation light to correct apparent fluctuations in fluorescence is a very effective method, and since it uses the excitation light itself, it requires less hardware to be added to the device. It has the advantage that only a small amount is required.

However, by using this method of normalizing the total amount of reflected light detected, it is not possible to make accurate corrections according to the distance of the fluorescent site or the size of the viewing angle within the detection field of view. .

The present invention is intended to solve the above problems, and in addition to the conventional detection of only the spectral intensity of fluorescent light, it also makes it possible to observe a two-dimensional distribution of fluorescent light intensity (hereinafter referred to as a fluorescent image). It is an object of the present invention to provide a cancer diagnostic device using fluorescence detection that can also realize correction of excitation light intensity, irradiation distance, and angular variation.

[Means for solving problems]

To this end, the present invention diagnoses tumors by irradiating excitation light onto a predetermined region of a living body into which a fluorescent substance with strong affinity for tumors has been injected in advance, and detecting the fluorescence generated by the irradiation. In a cancer diagnostic device, an excitation light irradiation means for irradiating excitation light, an irradiation means for irradiating diagnostic illumination light, an image guide for observing the irradiated area, and an output of the image guide as a first image. and a branching means for branching into a second image; a television camera for capturing the first image; a high-sensitivity imaging means for capturing the second image; inputting output signals of the television camera and the high-sensitivity imaging means;
A signal processing means that performs predetermined processing on the output signal of the high-sensitivity imaging means and then superimposes it on the output signal of the television camera to create image information; an excitation light irradiation means; an illumination light irradiation means; The present invention is characterized by comprising a timing controller that controls operations according to predetermined timing.

[Effect]

The present invention provides an optical filter that selectively transmits excitation light;
Using an optical filter that selectively transmits the fluorescent light from the HPD, the fluorescent light and reflected light images are separated and captured independently by a high-sensitivity camera. Standardization using a dimensional image enables accurate correction that is not influenced by the geometrical conditions of the fluorescent site within the detection field of view, and can also correct apparent unnecessary fluctuations in fluorescent intensity.

〔Example〕

Examples will be described below with reference to the drawings.

FIG. 1 is a block diagram showing an embodiment of a cancer diagnostic device using fluorescence detection according to the present invention, in which 401 is a timing controller, 403 is a white light source, 405 is a spectrometer, and 406 is a white light source.
is a high-sensitivity camera, 407 is a spectral image, 408 is an analysis circuit, 409.410 is a monitor, 411 is a tissue surface, 4
12 is a laser light source, 413 is an endoscope, 414 is a switching device, 415 is a diagnostic light source, 416 is a treatment light source, 417.
418 and 420 are light guides, 419 is an image guide, 430 is a splitter, 433 is a color camera, 434 is a fluorescent image processing system, and 437 is a screen composition circuit.

In the figure, an endoscope 413 is inserted into a site suspected of being a lesion in a patient who has previously been injected with HPD intravenously through a blood vessel. The endoscope 413 is equipped with light guides 417, 418, 420 and an image guide 419. The light guide 418 guides the light from the white light fA403 to the affected area and irradiates the tissue 411. On the other hand, the diagnostic light and treatment light from the laser light source 412 pass through the light guide 417 and pass through the group! t
i411 is irradiated. Laser light [412 is treatment light 'a
416, a diagnostic light a415, and a switching device 414, and the operator can switch the output light according to diagnosis and treatment. The light guide 420 is a biological Mi
This is an optical fiber for detecting the spectrum of fluorescence from textiles. This is connected to a spectrometer 405 in a fluorescence spectrum processing system 409. From the spectrometer 405, HPD
In order to observe the fluorescence spectrum, a spectrum image 407 in the 600-700 nm band is output. Since the intensity of the spectral image is very weak, a high-sensitivity camera 406 is used for this imaging. Output video signal 42 of high sensitivity camera 406
1 is input to an analysis circuit 408 , which converts the spectral image 407 into a spectral waveform and outputs it to a monitor 409 .

The image guide 419 is a fiber bundle for observing the irradiated area. The optical image outputted from here is split by a splitter 430, and each color camera 43
3 and a fluorescent image processing system 434. The color camera 433 is for observing normal endoscopic images, and outputs a color video signal 435. A fluorescent image processing system 434 outputs a fluorescent image signal 436 6
In the image synthesis circuit 437, a fluorescent image signal 436 is superimposed on the color video signal 435, and on the monitor 410, the fluorescent image mapped in pseudocolor on the color image can be observed. .

In this way, according to this embodiment, the fluorescence spectrum, color image, and fluorescence image can be viewed simultaneously on the monitor.

Next, control by the timing controller 401 will be explained.

As mentioned above, in this device, normal endoscopic diagnosis using color images and diagnosis using fluorescent information proceed simultaneously. Therefore, the white light source 403 and the laser light source 412 irradiate the tissue in a time-sharing manner so that the illuminating white light does not affect the fluorescence spectrum. Furthermore, the high-sensitivity camera 406 collects light in synchronization with the irradiation of excitation light, and closes its shutter during other periods to protect it from strong illumination light.

FIG. 2 is an operation timing chart of the white light source 403, the laser light source 412, and the high-sensitivity camera 40b.
FIG. 3 is an operation waveform diagram of a high-sensitivity camera shank.

In the figure, the operating cycle is set to 1/30 seconds, which is synchronized with the frame frequency of the television. A timing signal 402 necessary for this operation is supplied from a timing controller 401. As described later, the fluorescent image processing system 43
4 also includes a high-sensitivity camera, which performs the same imaging operation as the high-sensitivity camera 406 according to the chart in FIG.

Next, the fluorescent image processing system 43 which is a characteristic part of the present invention
4 will be explained in more detail.

FIG. 3 is a diagram showing an embodiment of the fluorescent image processing system 434, in which 601 is an optical filter, 603 is a high-sensitivity camera, and 603 is a high-sensitivity camera.
05 is a level slicer.

In the figure, an image 431 branched by a branch 430
is an optical filter 601 with a pass band of approximately 630±10 nm.
The reflected light image is removed and only the fluorescent image 602 is obtained. This is according to the chart shown in Figure 2.
The image is captured by a high-sensitivity camera 603 that performs an imaging operation.

The fluorescent image signal 604 is converted by a level slicer 605 into a binary signal of "1" when it is above a predetermined value and "0" when it is below a predetermined value, and output as a binary fluorescent image signal. . This signal is superimposed on the color video signal 435 in the screen composition circuit 437, and is displayed on the monitor 4.
10 is displayed on the screen.

The embodiment shown in FIG. 3 does not normalize the intensity of the fluorescent image using the reflected light image, and the rough position and intensity of the fluorescent light can be known just by this.

However, under actual diagnostic conditions, accurate diagnosis becomes difficult due to the above-mentioned apparent fluctuations in fluorescence intensity.

FIG. 4 is a block diagram showing another embodiment of a fluorescent image processing system including a standardization function to solve this problem, in which 701 is a half mirror, 1702 is a mirror, 705.7
06 is an optical filter, 709 is a high-sensitivity camera, 710 is a timing signal source, 714 is an A/D converter, 716 is a delay circuit, 718 is a divider, 720 is an image memory, 722
is a level slicer.

In the figure, an optical image 431 that has entered a fluorescent image processing system 434 is displayed on a half mirror 701 and a mirror 702.
is divided into two parallel images 703 and 704. Each of these images has a passband of approximately 405+5n.
m and 630±10 nm optical filter 705.70
6, and a spatially separated parallel fluorescence image 708 and reflected light image 707 are obtained as outputs. These two images are formed at different positions on the imaging surface (photocathode) of the high-sensitivity camera 709, respectively.

FIG. 5 is a diagram schematically showing an image on the imaging surface. In FIG. 0, S is the imaging surface, R is the scanning area, L is the scanning M line, and Fl
is a fluorescent image and R1 is a reflected light image.

In the figure, the difference in scanning time between arbitrary corresponding points Pr and Pa between the fluorescent image Fl and the reflected light image R1 is T.
Therefore, the high-sensitivity camera output video signal 71 in FIG.
2, the time difference T.

The signals of corresponding points of the two images are obtained at .

This signal is converted into a digital signal 7' by an A/D converter 714.
15. Next, the delay time T. The digital signal 715 is delayed by the delay circuit 716 having the following. As a result, signals corresponding to P and R7 are simultaneously obtained at the input terminal of the divider 718, and the division 'C1:PF/PR is executed. Therefore, a normalized image can be obtained by the output signal 719 of the divider 718. Image memory 72
0 takes in the normalized image part from the signal 719 and performs processing such as positioning that is necessary for later synthesis with the color image 435 (see FIG. 1). The normalized image signal 721 is binarized by a level slicer 722 and output as a binarized fluorescent signal 436. According to this method, it is possible to capture two images using only one very expensive high-sensitivity camera.

6th [Z] is a diagram showing another embodiment of the fluorescent image processing system 434, and the same numbers as in FIG. 4 indicate the same contents. Note that 723 is a small motor.

This embodiment differs from the case shown in FIG. 4 only in that two optical filters 705 and 706 are switched over time by mechanical means. This is useful when the imaging aperture of a high-sensitivity camera is small or when a large (and therefore high-resolution) fluorescence image is required, rather than separating the two images spatially as shown in Figure 4. Separated by time.

In the figure, filters 705 and 706 are switched by a small motor 723 controlled by a timing signal source 710 to obtain a fluorescent image and a reflected light image every frame. The subsequent processing is the same as that shown in FIG. However, the delay time in the delay circuit 716 is simply changed from To to one frame period (1/30 second). This is because the time difference on the signals of the corresponding points PF and Pa of the two images is TD in FIG. 4 and 1/30 second in FIG. 6. FIG. 7 shows a timing chart of signals at each part of the sixth leap.

Color video signal 435 and binarized fluorescent signal 436
As a result of the synthesis, a distribution of fluorescent images mapped onto a color image is observed on the monitor as schematically shown in FIG.

Although the embodiments of the present invention have been described above in detail using the drawings,
Modifications and applications of the present invention are not limited to the above-mentioned embodiments.
Various configurations are possible. In particular, regarding optical systems and non-life insurance systems, for example, the light guide 420 in FIG.
The method of guiding this to the spectrometer 405 and the high-sensitivity camera 406 for detracting the spectral image 407 are shared with the high-sensitivity camera for fluorescence imaging by time division or space division on the imaging surface, and the hardware You may also try to reduce the

〔Effect of the invention〕

As described above, according to the present invention, excitation light for causing fluorescent light emission is irradiated to a predetermined part of a living body into which a fluorescent substance with strong affinity for tumors is injected in advance, and thereby Cancer diagnostic equipment that detects the intensity of the generated fluorescent light can display a fluorescent image mapped according to the intensity in real time on top of a color endoscope image, compared to the conventional method of diagnosing using only the intensity of the fluorescent light spectrum. As a result, it has become possible to obtain information that is extremely important for diagnosis, such as the exact location and form of cancer.
Apparent fluctuations in the detected fluorescence intensity can now be accurately corrected by two-dimensionally normalizing the fluorescence image with the reflected light image, solving the problem of intensity fluctuations that made diagnosis extremely difficult. can do.

[Brief explanation of drawings]

FIG. 1 is a block diagram showing the overall configuration of an embodiment of a cancer diagnostic device using fluorescence detection according to the present invention, and FIG. 2 is a diagram for explaining the operation timing of the device according to the embodiment of the present invention.
Fig. 3 is a diagram showing one embodiment of the fluorescent processing system, Fig. 4 is a diagram showing another embodiment of the fluorescent processing system, Fig. 5 is a diagram showing an image on the imaging surface, and Fig. 6 is a diagram showing an example of the fluorescent processing system. A diagram showing another embodiment of the fluorescent processing system, FIG. 7 is a diagram showing the operation timing chart in FIG. 6, FIG. 8 is a diagram showing an example of display on a monitor, and FIG. FIG. 10 is a diagram showing the apparatus, FIG. 10 is a diagram showing the positional relationship between the irradiation fiber and the detection fiber with respect to the tissue, and FIG. 11 is a diagram showing the relationship between the fields of view of the irradiation fiber and the detection fiber. 401... Timing controller, 403... White light source, 405... Spectrometer, 406... High sensitivity camera, 407... Spectrum image, 408... Analysis circuit, 409.410... Monitor , 411... Tissue surface, 412... Laser light source, 413... Endoscope, 41
4...Switching device, 415...Diagnostic light source, 416
... treatment light source, 417.418.420 ... light guide, 419 ... image guide, 430 ... splitter, 433 ... color camera, 434 ... fluorescence image processing system, 437.・Screen synthesis circuit, 601...
・Optical fiber, 603...High sensitivity camera, 701...
・Half mirror-1702...Mirror, 705.706
...Optical filter, 709...High sensitivity camera, 71
0... Timing signal source, 714... A/D converter, 716... Delay circuit, 718... Divider, 720
...image memory. Applicant: Ministry of International Trade and Industry Director-General, Agency of Industrial Science and Technology Iizuka IE Figure 3r
l ′t^Figure 3 Figure 3 Figure 7 I Tomi No. 721
”+2゜Figure 10Figure 11

Claims (8)

[Claims] (1) Cancer diagnosis, in which a tumor is diagnosed by irradiating excitation light onto a predetermined part of a living body that has been injected with a fluorescent substance that has a strong affinity for tumors, and detecting the fluorescence generated by the irradiation. In the apparatus, excitation light irradiation means for irradiating excitation light;
an irradiation means for irradiating diagnostic illumination light; an image guide for observing the irradiated region; a branching means for branching the output of the image guide into a first image and a second image; A television camera to take images and a second
A high-sensitivity imaging means that captures an image of A cancer diagnostic device using fluorescence detection, comprising a signal processing means for creating image information, and a timing controller for controlling the operations of an excitation light irradiation means, an illumination light irradiation means, and a high-sensitivity imaging means according to predetermined timing. . (2) The excitation light irradiation means utilizes fluorescence detection according to claim 1, which comprises a first pulsed light source that generates excitation light and a first light guide that transmits the excitation light. Diagnostic equipment. (3) The illumination light irradiation means utilizes fluorescence detection according to claim 1, which comprises a second pulsed light source that generates illumination light and a second light guide that transmits illumination light. Cancer diagnostic equipment. (4) The timing controller periodically cuts off the output light of the second pulsed light source, and synchronizes with this operation, the timing controller
A cancer diagnostic apparatus using fluorescence detection according to claim 1, wherein the pulsed light source is controlled to emit light and the high-sensitivity imaging means is controlled to perform an imaging operation at the same time. (5) The high-sensitivity imaging means utilizes fluorescence detection according to claim 1, wherein the high-sensitivity imaging means includes an optical filter for selectively transmitting fluorescence from a fluorescent substance from the second image. A cancer diagnostic device. (6) The high-sensitivity imaging means includes a first optical filter for selectively transmitting the fluorescent light from the fluorescent substance from the second image, and a first optical filter for selectively transmitting the fluorescent light from the fluorescent substance, and the second image for transmitting the reflected image of the excitation light from the living body. a second optical filter for selectively transmitting the image; and a first optical filter according to control from the timing controller.
and switching means for alternately switching the second optical filter, and the signal processing means is configured to increase the intensity of the fluorescent image signal imaged through the first optical filter by the reflected light image signal imaged through the second optical filter. A cancer diagnostic device using fluorescence detection according to claim 1, which is standardized as follows. (7) The high-sensitivity imaging means includes a branching means for branching the input second image into a third image and a fourth image, and a branching means for selectively transmitting fluorescent light from the third image. a first optical filter; and a second optical filter for selectively transmitting the reflected light from the living body of the excitation light from the fourth image.
an optical filter, a high-sensitivity camera for imaging the transmitted light of the first and second optical filters, and a first and second optical filter.
Equipped with an optical system that guides the light transmitted through the optical filter to a position on the imaging screen of the high-sensitivity camera that does not overlap with each other,
The signal processing means utilizes the fluorescence detection described in claim 1, which normalizes the intensity of the fluorescence image signal included in the output signal of the high-sensitivity camera for each corresponding region using the reflected light image signal. Diagnostic equipment. (8) The cancer diagnostic device using fluorescence detection according to claim 1, wherein the fluorescent substance is hematoporphyrin (HPD), and the wavelength of the excitation light is approximately 405 nm.