JPH0325166B2 - - Google Patents

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is directed to a hematoporphyrin derivative (hereinafter referred to as HpD) that is easily accumulated in cancer cells and has a cell-killing effect when excited by light. Cancer treatment is possible by irradiating a fluorescent substance with a laser beam and selectively necrotizing only cancer cells using a photochemical reaction between the fluorescent substance and the laser beam. It relates to a cancer diagnosis and treatment device that diagnoses cancer by measuring distribution and intensity, and in particular can determine whether or not treatment by photochemical reaction is being performed accurately during cancer treatment. The present invention relates to a cancer diagnosis and treatment device that can improve reliability and functionality.

[Conventional technology]

Diagnosis and treatment of cancer involves absorbing a fluorescent substance with a strong affinity for cancer, such as HpD, into the lesion area in advance, and then irradiating this area with laser light, which involves a photochemical reaction between the fluorescent substance and the laser light. A cancer diagnosis and treatment method and apparatus have been proposed in which cancer cells are selectively necrotized by using the method (Japanese Patent Application Laid-Open Nos. 59-40830 and 1983-40869).

FIG. 6 is a diagram showing the basic configuration of the conventional diagnostic treatment device proposed above, in which 1 indicates the tissue surface, 2
is an image guide, 3 to 5 are light guides, 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 and 14 are monitors, 15 is a fiber bundle, 16 is a video signal, 17
18 is an endoscopic diagnosis system, and 18 is a photochemical reaction diagnosis and treatment system.

The apparatus shown in FIG. 6 is a conventional endoscopic diagnostic system 17.
and photochemical reaction diagnosis and treatment systems. The fiber bundle 15 is incorporated into an endoscope and inserted into a site suspected of being a lesion in a patient who has previously been intravenously injected with HpD.

The endoscopic diagnosis system 17 includes a white light source for illuminating the tissue surface, 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 that captures the image of the tissue surface 1. Monitor 13 that displays the image obtained by shooting with 6
It consists of

On the other hand, the photochemical reaction diagnosis and treatment system 18 is provided with a laser light source 8 that outputs pulsed laser light by switching between diagnostic light (405 nm) for diagnosis and therapeutic light (630 nm) for treatment. These lights are guided to the affected area by the light guide 4 and irradiated thereon. Fluorescent light generated by irradiation with a diagnostic laser beam during diagnosis is guided to a spectrometer 9 by a light guide 5. A fluorescence spectrum image 10 obtained by the spectrometer 9 is photographed by a high-sensitivity camera 11, and this output video signal 16 is processed by an analysis circuit 12 to be graphically displayed and displayed on a monitor 14 as a spectrum waveform. The spectral image 10 shows a bimodal shape of 630 nm and 690 nm characteristic of HpD fluorescence, and in order to observe this spectrum, the spectral wavelength range of the spectrometer 9 is
It is set at 600-700nm.

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 surface 1 in a time-sharing manner. The fluorescence spectrum analysis system from the spectrometer 9 to the monitor 14 also operates intermittently in synchronization with the laser beam irradiation.

With this device, during diagnosis, the operator can simultaneously view the tissue image on the monitor 13 and the fluorescence spectrum waveform on the monitor 14 while searching for the location of cancer, and if cancer is discovered, the excitation light can be switched to treatment. Treatment can be performed immediately.
This treatment is performed by selectively causing necrosis of only the cancerous area through a photochemical reaction between HpD remaining in the cancerous area and therapeutic light. Furthermore, when confirming fluorescence during diagnosis, since 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. In particular, it has the potential to greatly contribute to the diagnosis and treatment of early-stage cancer.

The wavelength of the treatment light was set to 630nm because, among the several absorption bands of HpD, absorption by blood is lowest at this wavelength, allowing the laser light to reach deep into the tissue, making it possible to treat deep cancers. Because you can. Also, the wavelength of the diagnostic light was set to 405nm.
This is because the absorption of HpD is large at this wavelength, and the fluorescence unique to HpD can be efficiently generated.

[Problem that the invention seeks to solve]

As mentioned above, conventional cancer diagnosis and treatment devices are
Diagnosis and treatment are carried out by utilizing the affinity for cancer. In particular, in treatment, in addition to the affinity, the cell-killing effect when photoexcited is effectively utilized.

As a principle of treatment, the following mechanism is generally considered to be correct. In other words, by 630nm wavelength light
HpD is energetically excited and this energy is transferred to oxygen in cancer cells. Oxygen, which is initially in the ground state of energy, is excited and activated by the energy transferred from this HpD. Cancer tissue is strongly affected by this oxygen activity and becomes necrotic. According to this principle, cancerous areas where a large amount of HpD accumulates undergo necrosis, and the influence of active oxygen can be virtually ignored in normal areas where HpD accumulates less. As a result, photochemical reaction-based therapy can destroy only cancer without affecting normal tissues, so it can be said to be a safe and painless method for patients. Moreover, when administered to humans, HpD has no side effects other than mild skin irritation when exposed to direct sunlight, so this treatment is becoming increasingly popular. However, at the same time, we are also experiencing new problems.

Even if the dosage of HpD is the same for the same disease state, and the laser irradiation conditions (wavelength, laser energy per pulse, pulse repetition, irradiation time, etc.) are the same, the treatment results will not necessarily be the same. The problem is that even if the treatment is effective for some patients, it is not so effective for other patients. This is thought to be due to the fact that the amount of HpD retained, the amount of oxygen, etc. differ between patients, for example, between young and old patients. After laser irradiation, 1-3
The fact that it is difficult to confirm the therapeutic effect until several days later is both inconvenient and worrying. It is desirable that the outcome of treatment can be predicted with sufficient accuracy during laser irradiation.

The present invention is intended to solve the above problems,
It is an object of the present invention to provide a cancer diagnosis and treatment device that can predict the effects of treatment with sufficient accuracy.

[Means for solving problems]

The cancer diagnosis and treatment device of the present invention uses a substance that has an affinity for cancer cells and has a fluorescent or cell-killing effect when excited by light, and cells containing this substance are irradiated with a light source device. An apparatus for diagnosing and treating cancer, comprising: a spectroscope for separating fluorescence obtained by optically exciting the substance; an imaging means for converting the spectrum from the spectrometer into a video signal; a photodetector sensitive to light of a specific wavelength, and an imaging means or a display means for displaying the output from the photodetector, and at the time of diagnosis, fluorescence obtained by exciting the substance with excitation light of a first wavelength. It spectrally spectrally displays a spectral image, and during treatment, it is excited with excitation light of a second wavelength, and light of a specific wavelength emitted from active oxygen in cancer tissue is spectrally detected and displayed.

[Effect]

The principle of the present invention is that infrared light of a specific wavelength (wavelength
1.27 μm) to monitor the treatment status. The process in which HpD is excited by laser light and oxygen is activated by this energy will be explained with reference to FIG. 4 using an energy diagram.

When irradiating HpD with 630nm wavelength laser light,
HpD is excited from the S ₀ state of energy to the S ₁ state. The S ₀ and S ₁ states contain fine structural components of vibrational energy and rotational energy, creating a band-like energy distribution. Laser light with a wavelength of 630 nm is used for treatment because among the several absorption bands of HpD, absorption by blood is lowest at this wavelength. This is because it can be expected to treat deep cancer. HpD in S ₁ state is equal to other energy state T ₁
It transfers energy to oxygen in the cell through O ₂ (triplet ³ O ₂ state). Oxygen is excited to the singlet state ¹ O ₂ by this energy and becomes active. This active oxygen acts on cancer tissue and causes necrosis of the cancer tissue. In other words, cancer treatment becomes possible. 1.27μm
Infrared light is obtained as a result of relaxation from a band-like level with an energy of ¹ O ₂ and a vibrational quantum number v = 0 to a level with an energy of ³ O ² and a vibrational quantum number v = 0. In other words, 1.27μm light is light generated from oxygen ( ¹ O ₂ ) in the active state, so if we detect this 1.27μm light and evaluate its intensity, it will be proportional to this.
This means that the number of ¹ O ₂ in existence can be estimated. As a result, by measuring 1.27 μm light during laser light irradiation treatment, it is possible to judge whether or not the light treatment is being performed smoothly.

〔Example〕

The present invention will be explained below based on examples.

FIG. 1 is a configuration diagram of a portion of a cancer diagnosis and treatment device related to the present invention. The overall device is a development of the configuration shown in FIG. 6, which follows the endoscopic diagnosis system of No. 17 as it is, and adds new functions to the photochemical reaction diagnosis and treatment system of No. 18. Therefore, FIG. 1 shows only the photochemical reaction diagnostic treatment system to which this new function of the present invention is added, and the same numbers as in FIG. 6 indicate the same contents. In the figure, C is the lesion area, 3
1 and 33 are reflecting mirrors, 32 is a diffraction grating, 34 is a shutter, 35 is an image intensifier tube, 3
6 ₁ is a photocathode, 36 ₂ is a fluorescent surface, 37 is an imaging lens, 41 is an image intensifier tube drive circuit, 42 is a photodetector, 43 is a gate circuit, 44 is an amplifier, 45 is an output meter, 47 is a timing control circuit.

At the time of diagnosis, a pulsed laser beam with a wavelength of 405 nm generated by a laser light source 8 is applied to the lesion area C of a patient who has been intravenously injected with an appropriate amount of HpD in advance through the light guide 4.
irradiate through. At this time, fluorescence is generated from the lesion C and is guided to the spectrometer 9 through the light guide 5. The fluorescent light emitted from the output end of the light guide 5 diverges, is reflected by the reflecting mirror 31, and enters the diffraction grating 32. The light separated by the diffraction grating 32 is transmitted to the photocathode 3 of the image intensifier tube 35.
6 ₁ , and a spectral image of fluorescence is obtained at this position. Since the fluorescence spectrum is weak, the image intensifier tube 35
The multiplied fluorescence spectrum image is formed on the fluorescent screen ₃₆₂ . This spectral image on the phosphor screen 36 ₂ is photographed by a high-sensitivity camera 11 , and this output video signal 38 is subjected to signal processing in an analysis circuit 12 and then displayed as a spectrum as waveform A on the TV monitor 14 . Here, the shutter 34 is provided to protect the photocathode ₃₆₁ of the image intensifier tube 35 from strong light irradiation.
In case of rare cuts, it is used in the open state (during treatment, it is used in the closed state as strong therapeutic laser light is incident). Image intensifier tube drive circuit 4
Reference numeral 1 denotes a power source that supplies voltage necessary to operate the image intensifier tube 35. In the endoscopic diagnosis system, white light is irradiated to observe the lesion C, and this and 405 nm laser light are irradiated to the lesion C alternately in time. White light lesion C
Since the reflected light from the image intensifier tube 35 is strong, during white light irradiation, the voltage supply to the image intensifier tube 35 is stopped to stop the operation of the image intensifier tube 35. The imaging lens 37 converts the spectral image on the fluorescent screen 36 ₂ of the image intensifier tube 35 into the photocathode 36 ₁ of the high-sensitivity camera 11.
This is to form an image on top of the light beam, thereby capturing a spectral image with low loss.

The spectral image obtained on the monitor 14 is
If it is unique to HpD, the lesion C has
Since it was found that HpD is contained, and HpD has a strong affinity for cancer, it is presumed that the lesion C is likely to be cancerous.

FIG. 2 shows a timing chart of the apparatus of the present invention employed at the time of diagnosis.

In the figure, timing control circuit 47
Pulse width to trigger the laser light source 8
10μs, voltage 5V pulse with a repetition rate of 60Hz,
Therefore, it is issued every 16.7ms. About 1 μs later, a diagnostic laser beam with a width of about 5 ns is generated. HpD
Fluorescence is obtained at approximately the same time as the laser light. The white light pulse for observing the lesion C is located in the middle of the repeated laser pulses, and is located at the middle of the repeated laser pulses.
In relation to 1.27 μm light detection, the time conditions are defined as shown in Figure 2. The image intensifier tube gate signal operates the image intensifier tube only when HpD fluorescence is detected (ON state).
This is to stop the operation (OFF state) to protect the image intensifier tube during white light pulse irradiation. The image intensifier tube gate signal is sent to the timing control circuit 4.
Image intensifier tube drive circuit 4 from 7
1, and the above ON/OFF operation is performed by the image intensifier tube drive circuit 41.

During treatment, the wavelength from the laser light source 8 is set to 630nm.
The pulsed laser beam of this wavelength is irradiated to the lesion C through the light guide 4. Through the above-described process, photochemical reaction cancer treatment is performed between the 630 nm laser beam, HpD contained in the focal area C, and the focal tissue. During this 630nm laser beam irradiation, the lesion C
1.27 μm from active singlet oxygen ( ¹ O ₂ ) is released. The 1.27 μm light is guided to the spectroscope 9 through the light guide 5, diffracted by the diffraction grating 32, and then detected by the photodetector 42. Photodetector 42
For example, a germanium (Ge) detector with high sensitivity at 1.27 μm is used, and in some cases, a Ge photodetector cooled with a cooling medium such as liquid nitrogen is used to increase the S/N ratio. The output signal from the photodetector 42 is amplified by an amplifier 44, and its output is read out by an output meter 45. The gate circuit 43
This is to accurately detect 1.27μm light.
That is, light with a wavelength of around 1.27 μm includes strong infrared fluorescence from HpD or from the focal living body in addition to the above-mentioned relaxed light from ¹ O ₂ . These are generated almost at the same time as the laser beam, whereas the relaxation light from ¹ O ₂ is generated after a complicated process as shown in Figure 4, so it lags the laser beam by about 1 ms. (Yusuke Kuroda: Basic research on laser photochemical therapy, Journal of the Japanese Society of Laser Medicine, 6 [4], P27 (1983)
reference). Therefore _, in order to accurately detect the 1.27 μm light emitted from ¹ O ₂ ^, the photodetector must
It is necessary to set the gate time so that it operates only when 1.27 μm light is emitted.

FIG. 3 shows a timing chart of the device during treatment. Same wavelength as during diagnosis
630nm laser light is about 1μs from the laser trigger
Occurs late. HpD at almost the same time as the laser beam
Infrared fluorescence is generated from the living tissue of the lesion C. The gate of the photodetector 42 is turned on at the time when infrared fluorescence emission ends, and before the white light pulse is emitted.
It will be turned off. In Figure 3, from the laser trigger
An example is shown in which it turns ON after 0.5ms and lasts for 2ms. However, it is expected that the time at which the emission of 1.27 μm light from ¹ O ₂ starts will differ slightly depending on the target lesion C, so it should be possible to adjust this gate time variably depending on the target. is desirable.
It is necessary that the gate ON time can be varied within a range that does not overlap with the white light pulse and the infrared fluorescence emission time. This is because when the emission time of the white light pulse overlaps with the emission time of the white light pulse, the resulting infrared fluorescence from the lesion C interferes with the detection of the 1.27 μm light from ¹ O ₂ . The 1.27 μm light from ¹ O ₂ is detected within the gate time as shown in Figure 3.

The output meter 45 may be one that can read the average value of the 60 Hz optical signal, and may be, for example, an ammeter that displays an rms value. The output signal of the amplifier 44 is sent to the analysis circuit 12 through a path 46, where the signal is processed and its intensity can be displayed on the monitor 14 as shown in waveform B. In the figure, two monitors are used to diagnose each
Although a method of displaying the spectrum obtained during treatment is shown, it is also possible to display the spectrum during diagnosis and treatment on one monitor by signal processing by the analysis circuit 12. In the description of the above embodiment, the repetition frequency of the laser pulse was 60Hz, but the present invention is not limited to this.
The frequency may be a fraction of 60Hz, for example, 30Hz, 15Hz, 7.5Hz, etc.

FIG. 5 is an example of the laser light source 8 shown in FIG. 1, which is a diagram showing an example of a pulsed light source that can be switched for diagnosis and treatment. In the figure, the part surrounded by the broken line indicated by 24 is the part that generates the second laser light pulse of 630 nm, and the part surrounded by the broken line indicated by 23 is the part that generates the second laser light pulse of 630 nm.
This is the part that generates the first laser light pulse of 405 nm.

The excimer laser 26 is commonly used by the second pulsed light source 24 and the first pulsed light source 23, and
A second pulsed light source 24 emits light with a wavelength of 630 nm using an ethanol solution of the dye Rhodamine 610.
Dye laser DL2 (630nm), first pulsed light source 23 A first dye laser that emits light with a wavelength of 405nm using a toluene and ethanol solution of dye PBBO.
It is possible to excite DL1 (405 nm).
L4 and L5 are focusing lenses, M1 and M4 are semitransparent mirrors, and M2 and M3 are total reflection mirrors, respectively. The switching section 25 is a shutter having two openings 25a and 25b. It can be moved by manual operation, and during treatment, it forms an optical path of the excimer laser 26, aperture 25a, and lens L4, and excites the dye laser DL2.
At the time of diagnosis, an optical path is formed between the excimer laser 26, the aperture 25b, and the lens L5, and the dye laser DL1 is excited.

The oscillation wavelength of the excimer laser 26 is 308 nm, the pulse width is 30 ns, and the energy is variable from several mJ to 100 mJ.
It is caused to repeatedly oscillate at a frequency of Hz or an integer fraction thereof.

〔Effect of the invention〕

As described above, according to the present invention, the following effects can be achieved.

The reliability of photochemical reaction cancer treatment can be improved. The reliability of phototherapy can be improved because it is possible to monitor the 1.27 μm light intensity, which indicates that the treatment is being performed during phototherapy. The intensity of this 1.27μm light varies depending on parameters such as the lesion area C, HpD concentration, and laser light intensity, so the 1.27μm light intensity obtained from the device should be calibrated in advance for each case. is desirable. If the 1.27 μm light intensity obtained during phototherapy is low compared to this calibration value, increase the laser light energy or use the light guide 4 that passes the laser light.
The laser beam can be brought closer to the lesion C to increase the laser beam energy density on the tissue surface, which can be used to improve accurate therapeutic effects.

It becomes possible to examine the limitations of photochemical reaction cancer treatment methods. Photochemical reaction cancer therapy cures HpD cancer
It is assumed that exists. At present, although it has been demonstrated that HpD selectively accumulates in some representative types of cancer and can be used for phototherapy, it is not possible to treat all cancers.
It is not clear whether HpD is selectively accumulated or whether HpD is uniformly accumulated within cancer tissues. By using the device of the present invention, it becomes possible to study these problems, and it becomes possible to study ways to improve the reliability of photochemical reaction cancer treatment.

Even if HpD is sufficiently accumulated in cancer, irradiation with therapeutic laser light may not always provide sufficient treatment. This seems to be a problem that is probably related to the individuality of living organisms. Certain substances in the body, such as pitamine A and vitamin E, are known to reduce the number of ¹ O ₂ molecules. Additionally, the amount of oxygen supplied differs between areas with high blood flow and areas with low blood flow. In this way, since conditions differ microscopically depending on each living organism, it is expected that the therapeutic effect will also be affected. The present invention can also be used to solve such problems and to study how to improve the reliability of photochemical reaction cancer treatment.

In the above, substances (drugs) that have a strong affinity for cancer and have a cell-killing effect when photoexcited,
Although HpD was specified and explained, the device of the present invention is HpD.
The present invention is not limited to HpD, and can be similarly used for substances other than HpD, such as pheophobide a, metal phthalocyanine, and chlorophylls. These substances are
Like HpD, it has a high affinity for cancer, and when it is photoexcited, it causes necrosis of cancer through the action of active oxygen ( ¹ O ₂ ) in cancer tissue. Similar to HpD, 1.27 μm light is generated by relaxation of ¹ O ₂ . However, since the absorption wavelength of these substances is different from that of HpD,
It is necessary to change the wavelength of the treatment laser light.

[Brief explanation of the drawing]

Fig. 1 is a diagram showing the configuration of the photochemical reaction cancer diagnosis and treatment system of the device of the present invention, Fig. 2 is a diagram showing a timing chart during diagnosis by the device of the present invention, and Fig. 3 is a timing chart during treatment by the device of the present invention. Figure 4 showing
The figure is a diagram for explaining the emission process of infrared 1.27 μm light related to the present invention, Figure 5 is a diagram showing an example of a pulsed laser light source, and Figure 6 is a diagram showing the configuration of a conventional photochemical reaction cancer diagnosis and treatment device. FIG. 1...Tissue surface, 4, 5...Light guide, 8
... Laser light source, 9 ... Spectrometer, 11 ... High sensitivity camera, 12 ... Analysis circuit, 14 ... Monitor, 3
2... Diffraction grating, 34... Shutter, 35... Image intensifier tube, 36 ₁ ... Photocathode,
36 ₂ ...fluorescent surface, 37...imaging lens, 41...
...Image intensifier ear tube drive circuit, 42
...Photodetector, 43...Gate circuit, 47...Timing control circuit.

Claims (1)

[Claims] 1. Using a substance that has an affinity for cancer cells and has the property of fluorescent light emission or cell-killing effect when excited by light, and irradiating cells containing this substance with a light source device. An apparatus for diagnosing and treating cancer, which includes a spectroscope for separating fluorescence obtained by optically exciting the substance, an imaging means for converting the spectrum from the spectrometer into a video signal, and an identification device from the spectrometer. It is equipped with a photodetector sensitive to wavelength light and an imaging means or display means for displaying the output from the photodetector, and during diagnosis, the fluorescence obtained by exciting the substance with the excitation light of the first wavelength is spectrally analyzed. A cancer diagnosis and treatment device, characterized in that during treatment, it is excited with excitation light of a second wavelength, spectrally detects and displays light of a specific wavelength emitted from active oxygen in cancer tissue. . 2 The substance is a hematoporphyrin derivative (HpD), the specific wavelength light is 1.27 μm light, and the first wavelength excitation light that causes fluorescence emission is 405 nm wavelength.
2. The cancer diagnosis and treatment apparatus according to claim 1, wherein the pulsed light of 630 nm and the excitation light of the second wavelength that generates active oxygen in the cancer tissue are pulsed light of 630 nm. 3. The spectrometer includes an entrance part to which a light guide is attached that transmits light generated from the lesion, a reflecting mirror that folds back the light that has passed through the entrance part and reflects it in the direction of a diffraction grating, and a diffraction grating that spectrally separates the incident light. ,
2. The cancer diagnosis and treatment apparatus according to claim 1, further comprising an exit port for taking out the separated fluorescence spectrum and an exit port for taking out the separated light of a specific wavelength. 4. The photodetector for detecting the specific wavelength light is:
2. The cancer diagnosis and treatment device according to claim 1, which is a germanium detector sensitive to 1.27 μm wavelength light and can be cooled with a cooling medium such as liquid nitrogen. 5 The system for displaying the spectroscopic image of fluorescent light during diagnosis includes a shutter, an image intensifier tube, an imaging lens, a high-sensitivity camera, and an analysis circuit in this order at the exit port for extracting the fluorescent spectrum of the spectrometer. 2. The cancer diagnosis and treatment apparatus according to claim 1, wherein a spectral image of fluorescent light is displayed on a TV monitor after processing the output video signals of the high-sensitivity cameras in an analysis circuit. 6. The cancer diagnosis and treatment apparatus according to claim 1, wherein the shutter is opened to allow light to pass through when diagnosing cancer, and closed to block the passage of light during cancer treatment. 7 The system for spectroscopically detecting and displaying light of a specific wavelength during the treatment includes a photodetector attached to the exit port of the spectrometer for extracting light of a specific wavelength, and the output of the detector is amplified and then processed by an analysis circuit. specific wavelength light
The cancer diagnosis and treatment apparatus according to claim 1, which is displayed on a TV monitor. 8. When the excitation light of the second wavelength is irradiated to the lesion, the photodetector starts photodetection after the emission of pulsed infrared fluorescence from the substance or the lesion tissue stops, and detects the lesion. 2. The cancer diagnosis and treatment apparatus according to claim 1, wherein light detection is completed before the white light pulse used for partial observation is emitted.