JPH0358729B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to hematoporphyrin derivatives (hereinafter referred to as
Excitation light is irradiated to predetermined areas such as the patient's trachea or bladder, which have been injected with a fluorescent substance that has a strong affinity for tumors (such as HPD), to cause the fluorescence to emit. The present invention relates to a cancer diagnostic device that uses fluorescence detection to diagnose tumors based on the intensity of light.

[Conventional technology]

Conventionally, cancer diagnosis and treatment methods and devices have been proposed that utilize a photochemical reaction between laser light and a fluorescent substance that has a strong affinity for tumors such as HPD. Kaisho 59-40830,
Japanese Patent Publication No. 59-40869, USP No. 4556057).

FIG. 9 is a block diagram showing the basic configuration of a conventional diagnostic device. In the figure, 1 is a tissue surface, 2 is an image guide, 3, 4, and 5 are light guides, 6 is a color camera, and 7 is a white light source. , 8 is a laser light source, 9 is a spectroscope, 10 is a fluorescence spectrum image, 11 is a high-sensitivity camera, 12 is an analysis circuit, 13 and 14 are monitors,
15 is a fiber bundle, 17 is an endoscope system, and 18 is a photochemical reaction diagnosis and 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 incorporated into an endoscope, and is inserted into a site thought to be a lesion in a patient who has previously received intravenous injection of HPD. The endoscope system 17
a white light source 7 for irradiating the light, a light guide 3 that guides this light, an image guide 2 that guides an image of the tissue surface 1 to a color camera 6, and a color camera 6.
It consists of a monitor 13 that displays an image of the tissue surface 1 captured by the monitor 13.

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 patient 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 graphically processed by the analysis circuit 12 through arithmetic processing, and is displayed on the monitor 14 as a spectral waveform. 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 causing necrosis of only the cancerous area through a photochemical reaction between the HPD remaining in the cancerous area and the therapeutic light.

Furthermore, regarding confirmation of fluorescence during diagnosis,
Because the spectral waveform unique to fluorescence itself is directly observed, there is no confusion with autofluorescence from normal areas, making it easy to identify cancer, and making a major contribution to the diagnosis and treatment of early-stage cancer.

[Problems to be solved by the invention]

As mentioned above, conventional devices utilize HPD's affinity for tumors for diagnosis and treatment. In particular, for fluorescence detection from HPD during diagnosis,
A method of observing the spectral intensity is used. 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.

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

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 the fluorescent light can be observed, it changes greatly due to fluctuations in laser output, the distance from the irradiation port at the end of the endoscope to the tissue, and the irradiation angle, so it may be difficult to see the difference between normal and normal areas. It becomes very difficult to distinguish between the two parts.

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

By the way, regarding the above, in order to correct the apparent fluctuations in the spectral intensity, a method has been proposed that utilizes the reflected light of the excitation light (Japanese Patent Application No. 1983-
No. 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 tissue 1 to be irradiated, and from this point P (joules per unit) of excitation light is emitted toward the surface of the living tissue. Intensity of excitation light incident on the tissue
Iin is a function of the above-mentioned fluctuation factors P, l, and θ, such as Iin=Iin(P, l, θ). The amount of fluorescent light IF generated by this excitation light is expressed as follows.

IF=k ₀・Iin・ηF・n k ₀ : Constant unrelated to P, l, θ ηF : Fluorescent efficiency of HPD n : Concentration of HPD Note that the amount of fluorescent light (IF) is not exactly the same as the HPD concentration (n). Although there is no proportional relationship, the practical value of n (10 ^-5 ~
10 ^-6 mol/), an approximate proportional relationship holds true.

Letting If of the generated fluorescence IF enter the detection fiber and ηD the fluorescence detection efficiency, If=IF·ηD =k ₀ ·Iin·ηF·n·ηD. .eta.D is a function of the relative position (l, .theta.) between the fluorescent part and the detection fiber and the effective light focusing range S shown in FIG. The effective condensing 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 depending on the fluctuation of the irradiation fiber, etc., and is expressed as shown in the following equation.

ηD=ηD (l, θ, S) Furthermore, since the directivity of fluorescent light is isodirectional, ηD
is not included as a function.

On the other hand, the reflected light Ir entering the detection fiber is given by Ir=k ₁・Iin ・R ・η′D k ₁ : Constant unrelated to P, l, and θ R : Reflectance η′D : Detection efficiency of reflected light It will be done.

Strictly speaking, the reflectance R is a function of n, but for practical n where the concentration is very low, it can be considered almost constant, and has a value determined by the nature of the tissue.
Furthermore, regarding the comparison between ηD and η′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 fluorescent light, if necessary, if only this is separated and detected with a polarizing filter, the directivity conditions will be the same. become. Therefore, ηD=η′D is realized. Note that the difference in the focusing range due to the difference in wavelength between the reflected light (405 nm) and the fluorescent light (630 nm) is slight and can be regarded as a fixed factor, so that no practical problem arises.

Therefore, Ir= _k1・Iin・R・ηD.

When the detected fluorescent light intensity If is normalized by the detected reflected light intensity Ir, If/Ir=k ₂ ·ηF·n/R. Note that k ₂ is (k ₀ /k ₀ ), which is a constant that is unrelated to P, l, and θ. Therefore, If/Ir is proportional to the HPD fluorescence efficiency (ηF) and HPD concentration (n), and inversely proportional to the reflectance of biological tissue, and is a variable factor P, l, θ, S at the time of diagnosis. 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,
In addition to the conventional detection of only the spectral intensity of fluorescent light,
In addition to making it possible to observe a two-dimensional distribution of fluorescence intensity (hereinafter referred to as a fluorescence image), the intensity of excitation light,
The purpose of the present invention is to provide a cancer diagnostic device using fluorescence detection that can also correct irradiation distance and angle variations.

[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. a television camera that captures the first image; a television camera that captures a fluorescent image and a reflected light image of excitation light from the second image; The output signals of the television camera and the high-sensitivity imaging means are inputted to a high-sensitivity imaging means that standardizes the intensity using the reflected light image of the excitation light, and the output signals of the high-sensitivity imaging means and the output signals of the television camera are superimposed. The present invention is characterized in that it includes an image synthesizing means for creating image information based on the image information, and a timing controller for controlling the operations of the excitation light irradiation means, the illumination light irradiation means, and the high-sensitivity imaging means according to predetermined timing.

[Effect]

The present invention uses an optical filter that selectively transmits excitation light and an optical filter that selectively transmits fluorescent light from the HPD to separate the fluorescent light and reflected light images and capture the images independently using a high-sensitivity camera. ,
By normalizing the fluorescent image signal obtained from this into a two-dimensional image using the reflected light image signal, accurate correction that is not affected by the geometrical conditions of the fluorescent site within the detection field of view becomes possible, and the fluorescent intensity can be reduced. Apparently unnecessary fluctuations can also be corrected.

〔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, and 4
05 is a spectrometer, 406 is a high-sensitivity camera, 407 is a spectral image, 408 is an analysis circuit, 409, 41
0 is a monitor, 411 is a tissue surface, 412 is a laser light source, 413 is an endoscope, 414 is a switching device,
415 is a diagnostic light source, 416 is a therapeutic 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 has been 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 has a light guide 41
7,418,420 and image guide 419
is installed. The light guide 418 guides the light from the white light source 403 to the affected area and illuminates 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 the tissue 4
11. The laser light source 412 includes a therapeutic light source 416, a diagnostic light source 415, and a switching device 4.
14, and the operator can switch the output light according to diagnosis and treatment. The light guide 420 is an optical fiber for detecting the spectrum of fluorescent light from living tissue. This is connected to a spectrometer 405 in a fluorescence spectrum processing system 409. The spectrometer 405 outputs a spectrum image 407 in the 600-700 nm band in order to observe the HPD fluorescence spectrum. Since the intensity of the spectral image is very weak, a high-sensitivity camera 406 is used to capture this image.
is used. An output video signal 421 from the high-sensitivity camera 406 is input to an analysis circuit 408 , which converts the captured 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 irradiation area. The optical image output from this is split by a splitter 430 and supplied to a color camera 433 and a fluorescent image processing system 434, respectively. The color camera 433 is for observing normal endoscopic images, and outputs a color video signal 435. Fluorescent image processing system 434 outputs a fluorescent image signal 436. In the image synthesis circuit 437, the color video signal 435
In contrast, the fluorescent image signal 436 is superimposed, and a fluorescent image mapped in pseudocolor onto the color image can be observed on the monitor 410.

In this way, according to this embodiment, on the monitor,
You can view the fluorescence spectrum, color image, and fluorescence image at the same time.

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 receives 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 shows a white light source 403, a laser light source 412,
This is an operation timing chart of the high-sensitivity camera 406, and FIG.

In the figure, the operating cycle is set to 1/30 seconds, which is synchronized with the TV frame frequency. A timing signal 402 necessary for this operation is supplied from a tamming controller 401. As described later,
A high-sensitivity camera is also included in the fluorescent image processing system 434, and performs the same imaging operation as the high-sensitivity camera 406 according to the chart in FIG.

Next, the fluorescent image processing system 434, which is a feature of the present invention, 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 605 is a level slicer.

In the figure, an image 431 split by a splitter 430 has a reflected light image removed by an optical filter 601 with a pass band of approximately 630±10 nm, and only a fluorescent image 602 is obtained. This is imaged by a high-sensitivity camera 603 that performs an imaging operation according to the chart shown in FIG. 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 displayed on the monitor 410.

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, 702
is a mirror, 705, 706 is an optical filter, 70
9 is a high-sensitivity camera, 710 is a timing signal source,
714 is an A/D converter, 716 is a delay circuit, 71
8 is a divider, 720 is an image memory, and 722 is a level slicer.

In the figure, an optical image 431 entering a fluorescent image processing system 434 is converted into two parallel images 70 by a half mirror 701 and a mirror 702.
It is divided into 3,704. These images are directed to optical filters 705, 706 with passbands approximately 405±5 nm and 630±10 nm, respectively, and output spatially separated parallel fluorescent images 708.
A reflected light image 707 is obtained. 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 the figure, S is the imaging surface, R is the scanning area, and L
is a scanning line, FI is a fluorescence image, and RI is a reflected light image.

In the figure, the difference in scanning time between arbitrary corresponding points P _F and P _R between the fluorescent image FI and the reflected light image RI is T _D
It is. Therefore, in the high-sensitivity camera output video signal 712 of FIG. 4, signals of corresponding points of the two images are obtained at the time difference _TD .
This signal is converted into a digital signal 715 by an A/D converter 714. Next, the digital signal 715 is delayed by a delay circuit 716 having a delay time _TD . As a result, signals corresponding to P _F and P _R are simultaneously obtained at the input terminal of the divider 718, and the division P _F /P _R is executed. Therefore, the divider 71
A normalized image can be obtained by the output signal 719 of 8. Image memory 720 receives signal 71
The normalized image portion is taken in from 9 and subjected to processing such as positioning that will be necessary when combining it with the color image 435 later (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.

FIG. 6 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 uses two optical filters 705 and 706.
The only difference from the case shown in FIG. 4 is that the time switching is performed by mechanical means. When the imaging aperture of a high-sensitivity camera is small or when a large (and therefore high-resolution) fluorescent image is required, the spatially two-dimensional
Rather than dividing the images into two, they are separated temporally.

In the figure, a small motor 723 controlled by a timing signal source 710 operates a filter 705
706 to obtain a fluorescent image and a reflected light image for each 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 T _D to one frame period (1/30 seconds). This is because the time difference on the signals of the corresponding points P _F and _PR of the two images is T _D in FIG. 4 and 1/30 second in FIG. 6. FIG. 7 shows a timing chart of signals in each part of FIG. 6.

As a result of combining the color video signal 435 and the binarized fluorescence signal 436, a distribution of fluorescence 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 with reference to the drawings, modifications and applications of the present invention are not limited to the above-mentioned embodiments, and various configurations are possible. especially,
Regarding the optical system and the imaging system, for example, the light guide 420 in FIG.
The image 431 (or image 432) obtained from this is further branched and guided to the spectrometer 405, and the high-sensitivity camera 406 for capturing the spectral image 407 is used as a high-sensitivity camera for capturing fluorescence images. It may be shared with the camera by time division or space division on the imaging surface to reduce the amount of hardware.

〔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 uses a fluorescent image that is mapped according to intensity on top of a color endoscopic image, compared to the conventional method of making a diagnosis based only on the intensity of the fluorescent light spectrum. As a result of being able to observe in real time, it is now possible to obtain information that is extremely important for diagnosis, such as the exact location and morphology of cancer.Furthermore, apparent fluctuations in the detected fluorescent light intensity can be detected using fluorescent light. By two-dimensionally normalizing the image with the reflected light image, it becomes possible to perform accurate correction, and it is also possible to solve the problem of intensity fluctuations that have made diagnosis extremely difficult.

[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;
Fig. 2 is a diagram for explaining the operation timing of the apparatus according to the embodiment of the present invention, Fig. 3 is a diagram showing one embodiment of the fluorescent processing system, and 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, FIG. 6 is 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, FIG. 9 is a diagram showing a conventional cancer diagnostic device,
FIG. 0 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, 414...Switching device, 415...Diagnostic light source, 416...Treatment light source, 417, 418,
420... Light guide, 419... Image guide, 430... Branch, 433... Color camera, 434... Fluorescence image processing system, 437...
Screen composition circuit, 601... Optical fiber, 603...
...High sensitivity camera, 701...Half mirror, 70
2... Mirror, 705, 706... Optical filter, 709... High sensitivity camera, 710... Timing signal source, 714... A/D converter, 716...
...Delay circuit, 718...Divider, 720...Image memory.

Claims (1)

[Claims] 1. Diagnosis of a tumor is made by irradiating excitation light to a predetermined part of a living body into which a fluorescent substance with strong affinity for tumors has been injected in advance, and detecting the fluorescent light generated by the irradiation. The cancer diagnostic apparatus includes 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 a first output of the image guide. a branching means for branching into an image and a second image; a television camera for capturing the first image;
A high-sensitivity imaging means that separately captures a fluorescent image and a reflected excitation light image from the second image, and standardizes the intensity of the fluorescent image with the excitation light reflected image, and a television camera. An image synthesizing means receives the output signal of the high-sensitivity imaging means and creates image information by superimposing the output signal of the high-sensitivity imaging means and the output signal of the television camera, an excitation light irradiation means, an illumination light irradiation means, and a high-sensitivity A cancer diagnostic device that uses fluorescence detection and includes a timing controller that controls the operation of an imaging device according to a predetermined timing. 2. Cancer diagnosis using fluorescence detection according to claim 1, wherein the excitation light irradiation means comprises a first pulsed light source that generates excitation light and a first light guide that transmits the excitation light. Device. 3 The illumination light irradiation means comprises a second pulsed light source that generates illumination light and a second light guide that transmits the illumination light. Diagnostic equipment. 4. The timing controller periodically blocks the output light of the second pulsed light source, causes the first pulsed light source to emit light in synchronization with this operation, and controls the high-sensitivity imaging means to perform an imaging operation at the same time. A cancer diagnostic device using fluorescence detection according to claim 1. 5. The high-sensitivity imaging means utilizes fluorescence detection according to claim 1, which is equipped with an optical filter for selectively transmitting fluorescence from the fluorescent substance from the second image. diagnostic equipment. 6. The high-sensitivity imaging means includes a first optical filter for selectively transmitting fluorescent light from a fluorescent substance from a second image, and a first optical filter for selectively transmitting fluorescent light from a fluorescent substance from a living body, and a first optical filter for transmitting an image of excitation light reflected from a living body from a second image. The signal processing means includes a second optical filter for selectively transmitting the light, and a switching means for alternately switching between the first and second optical filters according to control from the timing controller, and the signal processing means transmits the light through the first optical filter. 2. A cancer diagnostic device using fluorescence detection according to claim 1, wherein the captured fluorescence image signal is intensity-normalized by the reflected light image signal captured through a second optical filter. 7. The high-sensitivity imaging means includes a branching means for branching an inputted second image into a third image and a fourth image, and a first branching means for selectively transmitting fluorescent light from the third image. optical filter,
a second optical filter for selectively transmitting the excitation light reflected from the living body from the fourth image; a high-sensitivity camera for capturing the transmitted light of the first and second optical filters; The signal processing means is equipped with an optical system for guiding the transmitted light of the first and second optical filters to positions on the imaging screen of the high-sensitivity camera where they do not overlap with each other, and the signal processing means is configured to process a fluorescent image signal included in the output signal of the high-sensitivity camera. 2. A cancer diagnostic device using fluorescence detection according to claim 1, wherein the intensity is normalized for each corresponding region using a reflected light image signal. 8 The fluorescent substance is hematoporphyrin (HPD)
The cancer diagnostic device using fluorescence detection according to claim 1, wherein the excitation light has a wavelength of approximately 405 nm.