JPWO2010090287A1 - Tumor tissue cell death inducer for tumor treatment - Google Patents

Abstract

It is extremely minimally invasive to tumor patients, especially malignant tumor patients, and is extremely unlikely to cause adverse events such as heat, burns, pain, or serious side effects in any race. It is safe and highly effective in preventing damage and minimizing not only the skin, but also the tumor cells deeper than the skin and malignant tumor tissues such as tumor foci, which are in the growth phase, can spontaneously die. A simple tumor treatment apparatus capable of indicating In the tumor treatment apparatus 1, the filter 16 a that absorbs, reflects, or scatters the wavelength of 1400 to 1500 nm of the emitted light from the near-infrared ray emission source 15 and transmits the near-infrared ray, the near-infrared ray emission source 15 and the near-infrared ray. It is arrange | positioned in the middle of the path | route with the tumor tissue 3 of the biological body 2 irradiated by (1).

Description

  The present invention relates to a device used for treating a tumor by irradiating a tumor tissue of a human or non-human animal, particularly a malignant tumor lesion, with near infrared rays.

  The most common cause of death among Japanese is malignant tumors such as cancer and sarcoma. This malignant tumor is a cause of high mortality worldwide, and for the purpose of its treatment, surgical treatment to remove the lesion, radiation therapy such as X-ray, electron beam, γ-ray irradiation to the lesion, Various treatment methods such as chemotherapy by administration of an anticancer agent and thermotherapy by infrared irradiation are administered alone or in combination.

  Each of these treatment methods is appropriately performed while observing adaptation to the patient, and produces a certain therapeutic effect. On the other hand, it often causes a serious side effect or an excessive burden on the patient. For example, surgical treatment not only inflicts physical burden on patients due to decreased immunity, tumor recurrence, morbidity of other diseases, mental burden, human burden, economic burden, social Various burdens such as burdens may be imposed. Such a burden can also occur in other treatment methods such as radiation therapy, chemotherapy, and hyperthermia.

  Among these therapies, hyperthermia is relatively less invasive than surgery, chemotherapy, and radiotherapy, and it is said that there are few serious side effects, but the malignant tumors to be treated are limited. There are still many problems to be overcome, such as large-scale and expensive equipment and facilities, and the burden on patients because they are heated by far infrared rays for a long time.

  Many of the commercially available infrared irradiation devices that are widely used for such thermotherapy are said to emit far infrared rays mainly from an integrated infrared radiation source, but actually the near infrared rays are also emitted considerably. In general, near infrared rays have higher energy than far infrared rays and are absorbed by the surface layer, and therefore have low permeability to the deep part of a patient's living body. For that reason, in order to sufficiently heat a lesion in the deep part of a living body of a patient with a commercially available infrared irradiation device, far infrared rays are irradiated for a long time or a strong output is required. As a result of having to be exposed to infrared rays containing a lot of near infrared rays for a long time, the total amount of energy irradiated on the surface of the patient's body becomes large, causing adverse events such as heat, burns, pain, dehydration, and fatigue May suffer. Further, if the wavelength is controlled or the output is reduced in order to reduce or avoid these adverse events, a sufficient therapeutic effect may not be obtained.

  Patent Document 1 discloses a laser treatment device that is used for cancer treatment by irradiating near-infrared rays of 904 nm. Such near-infrared light near 904 nm is absorbed at a very high rate by melanin that is colored on the skin surface layer, so even though it is a white race with a relatively small amount of melanin, it is not suitable for irradiation to the colored site skin with pigmentation. In addition, irradiation of the skin of colored people with much melanin is likely to cause adverse events such as burns, and is not suitable. In addition, near infrared rays in the vicinity of the wavelength are absorbed quickly by the melanin on the skin surface layer, and the wavelength is short and does not reach the deep part, so that it can act only on the extreme surface layer such as the epidermis. Furthermore, strong pain is developed in a patient whose portion to be irradiated is a colored portion, particularly a patient of a colored race. For this reason, it can be irradiated only at low power, and a dramatic tumor treatment effect cannot be expected. In addition, it cannot be avoided from unavoidable adverse events such as burns in colored areas of the skin.

US Pat. No. 5231984

  The present invention has been made to solve the above-mentioned problems, and is extremely minimally invasive to tumor patients, particularly malignant tumor patients, and is free of heat, burns, pain and serious side effects in any race. Such as tumor cells not only in the skin but also deeper than the skin, and in the growth phase of malignant tumor tissues such as tumor foci. An object of the present invention is to provide a simple tumor treatment apparatus that can cause cells to spontaneously die, is safe and can exhibit a high therapeutic effect.

  The tumor treatment device according to claim 1, which has been made to achieve the above object, absorbs, reflects, or scatters a wavelength of 1400 to 1500 nm in a light beam emitted from a near infrared radiation source. A filter that transmits near-infrared rays is arranged in the middle of the path between the near-infrared emission source and the tumor tissue of the living body irradiated with the near-infrared rays.

  The tumor treatment device according to claim 2 is the tumor treatment device according to claim 1, wherein the filter has an aqueous layer.

  A tumor treatment device according to a third aspect is the one described in the first aspect, wherein the near infrared wavelength range is 1000 to 1800 nm.

  The tumor treatment device according to claim 4 is the one described in claim 1, wherein the laser diode that emits the laser beam that is the emitted light, or the light emitting diode that emits the emitted light, a tungsten lamp, a halogen lamp, It is a xenon lamp, a carbon heater or a ceramic heater.

  The tumor treatment apparatus according to claim 5 is the tumor treatment apparatus according to claim 1, wherein the near-infrared ray emission source is an oscillation circuit that emits the emitted light in a pulsed manner or an emission circuit that continuously emits the emitted light, and a single time of the emitted light. It is connected to a timer for emitting a shot or a plurality of shots, a switch circuit for starting and stopping the emission, and / or an amplifier circuit for amplifying the output of the near-infrared emission source.

  A tumor treatment apparatus according to a sixth aspect is the one described in the first aspect, characterized in that the tumor treatment apparatus includes a pair or a plurality of pairs of the near-infrared ray emission source and the filter.

  The tumor treatment device according to claim 7 is the tumor treatment device according to claim 6, wherein the pair of the near-infrared ray emission source and the filter is attached to each distal end portion of one or a plurality of hand pieces. It is characterized by.

  The tumor treatment apparatus according to an eighth aspect is the one according to the seventh aspect, wherein a sapphire glass cooling window that contacts the living body is exposed on the surface of the handpiece in the middle of the path. It is characterized by being installed.

  The tumor treatment device according to claim 9 is the tumor treatment device according to claim 1, wherein the near-infrared ray emission source inserted into the inner space of the tip of a catheter to be inserted into the body of a human or non-human animal, The filter is covered.

  A tumor treatment device according to a tenth aspect is the one described in the first aspect, wherein the tumor tissue of the living body is a malignant tumor and / or a benign tumor of a human or non-human animal.

  The tumor treatment apparatus of the present invention is extremely minimally invasive and can treat benign or malignant tumors, particularly malignant tumors such as cancer and sarcoma, regardless of whether or not other treatments are performed. It is used for. This tumor treatment device has the potential to cause adverse events such as intense heat, burns, pain, and serious side effects, regardless of race or color. Low, can prevent normal cell damage to a minimum and treat malignant tumors by causing natural death of tumor cells deeper than the skin and malignant tumor tissues such as tumor foci Is.

  This tumor treatment apparatus has a simple structure and is small and portable, and can easily treat a tumor without complicated operations.

  Near-infrared rays have a shorter wavelength than far-infrared rays, so that they do not easily reach the deep tissue of the living body and are easily absorbed by the skin surface layer to cause adverse events such as burns. Nevertheless, such a tumor treatment apparatus does not cause such a problem. In particular, by providing a sapphire glass cooling window at the tip of the handpiece, the skin surface layer can be directly cooled, minimizing adverse events such as heat, pain, and burns even when irradiated with high power. be able to. Furthermore, by cooling the skin surface layer, the molecular movement of water molecules on the skin surface layer is suppressed, absorption of near-infrared light is minimized, and near-infrared light is transmitted deep into the living body without excessively raising the temperature of the surface tissue. It is possible to efficiently reach the tumor tissue.

  Even if the same site is irradiated with the high-power near-infrared ray several times by this tumor treatment apparatus, there is very little possibility of causing intense heat sensation, redness, pain, swelling and burns. In particular, if the irradiation conditions are mild enough to cause natural death of the tumor tissue, there are few adverse events and even pain. Therefore, it is possible to treat a malignant tumor by irradiating a plurality of times in a short time to dramatically reduce the proliferation of malignant tumor cells or kill the malignant tumor cells.

  According to this tumor device, the near-infrared ray is irradiated directly to the skin through the handpiece to efficiently reach the near-infrared ray to the skin and the tumor tissue inside the skin, or to the internal tissue deeper than the skin through the catheter. It is possible to irradiate near infrared rays directly and to make the near infrared rays reach the tumor tissue efficiently.

  In addition, according to this tumor treatment apparatus, even if the near-infrared irradiation is resumed for a malignant tumor that has recurred after being irradiated with near-infrared irradiation to a malignant tumor tissue, the heat resistance is not caused again. It is possible to dramatically reduce the proliferation of malignant tumor cells.

  According to this tumor treatment apparatus, since there is a low possibility of causing an adverse event, not only the physical burden on the patient is reduced, but also it can be easily treated without requiring special equipment or facilities, which contributes to a reduction in medical costs.

It is a figure which shows the outline | summary of the whole picture of the tumor treatment apparatus to which this invention is applied. It is a figure which shows the one part outline | summary of another tumor treatment apparatus to which this invention is applied. It is a figure which shows the one part outline | summary of another tumor treatment apparatus to which this invention is applied. It is a perspective view which shows the handpiece in another tumor treatment apparatus to which this invention is applied. It is the figure which quantified and showed the survival rate when near infrared rays were irradiated to the tumor cell using the tumor treatment apparatus to which this invention is applied. It is the figure which quantified and showed the survival rate when near-infrared rays were irradiated to another tumor cell using the tumor treatment apparatus to which this invention is applied. It is a graph which shows the correlation with the tumor tissue volume and elapsed days in the irradiation group of the near infrared rays to the breast cancer cell transplantation mouse | mouth using the tumor treatment apparatus to which this invention is applied, and the non-irradiation control group. Micrograph showing a state of staining tumor tissue excised on the 13th day of irradiation in the near-infrared irradiation group and the same day in the non-irradiated control group to the mouse transplanted with breast cancer cells using the tumor treatment apparatus to which the present invention is applied. It is. Breast cancer cell transplanted mice using the tumor treatment apparatus to which the present invention is applied Stained tumor tissue excised on the last irradiation day of irradiation group (37 days after irradiation) and the same day of non-irradiation control group It is a microscope picture which shows the state which carried out. It is a graph which shows the correlation with the tumor tissue volume in the irradiation group of a near infrared ray to another tumor cell transplantation mouse | mouth using the tumor treatment apparatus to which this invention is applied, and the non-irradiation control group, and elapsed days. Photomicrograph showing a state of staining tumor tissue excised on another day of irradiation in the near infrared irradiation group and on the same day in the non-irradiated control group to another tumor cell transplanted mouse using the tumor treatment apparatus to which the present invention is applied It is. The microscope which shows the state which dye | stained the tumor tissue extracted on the same day of the irradiation resumption last day of the irradiation group of near-infrared rays to another tumor cell transplantation mouse | mouth using the tumor treatment apparatus to which this invention is applied, and the non-irradiation control group It is a photograph. It is a figure which shows the correlation with the wavelength of 400-about 3000 nm, the irradiance when using the tumor treatment apparatus to which this invention is applied, and the absorption coefficient of melanin, hemoglobin, and water.

  1 is a tumor treatment device, 2 is a living body, 3 is a tumor tissue, 11 is an oscillation circuit, 12 is a timer, 13 is a modulation circuit, 14 is a switch circuit, 15 is a near infrared emission source, 16a and 16b are filters, and 17 is a lens. , 18 is a sapphire glass cooling window, 19a and 19b are coolers, 20 is near infrared, 21 is a cooler control circuit, 22 is a reflector, 23 is a gap, 24 is a double tube, 30 is a handpiece, 31 is a housing, 32 Is a switch, and 40 is a controller body.

  Hereinafter, examples of preferable modes for carrying out the present invention will be described in detail, but the scope of the present invention is not limited to these modes.

  A tumor treatment apparatus 1 of the present invention will be described with reference to FIG. 1 showing an embodiment. The tumor treatment device 1 is for selectively allowing only near infrared rays to reach the tumor tissue 3 of the living body 2.

  This tumor treatment apparatus 1 has an AlGaAs (aluminum, gallium, arsenic) laser diode, which is a near-infrared emission source 15, and a GaAs laser diode, and an emission direction of laser light, which is an emission beam including near-infrared rays emitted therefrom. A first filter 16a that absorbs wavelengths between 1400-1500 nm and wavelengths greater than 1800 nm to reduce transmission of wavelengths in that range, and wavelengths less than 1000 nm, preferably less than 1100 nm, and wavelengths outside that range And a second filter 16b that transmits only the light. A lens 17 and a near-infrared transmissive sapphire glass cooling window 18 in contact with the living body 2 are disposed at the tip of the filter 16b in the laser beam emission direction. Coolers 19a and 19b are respectively attached to the first filter 16a and the sapphire glass cooling window 18 which face each other while adjoining the laser diode 15.

  The first filter 16a has a water layer, for example, a cell such as quartz or glass filled with water. The water has a wavelength of 1400 to 1500 nm and a wavelength exceeding 1800 nm, preferably exceeding 1700 nm. By absorbing the wavelength, the transmission of the wavelength is reduced. The water layer may be distilled water, ion-exchanged water, tap water, electrolytes such as inorganic salts and organic salts, non-electrolytes such as sugars, such as physiological saline and Ringer's solution, monoliths such as methanol and ethanol. An aqueous solution in which one or more of additives such as alcohol and polyol such as ethylene glycol are dissolved may be used. If the thickness of the water layer in the filter 16a through which the laser beam passes is too thick, the heating in the tumor tissue 3 is reduced when the laser beam 20 is irradiated, whereas if the thickness is too thin, When the laser beam 20 is irradiated, the laser beam 20 is absorbed by the surface layer of the living body, the living body is overheated, and burns, thermal sensation, and pain are felt. The thickness is preferably about 0.5 mm to 2.0 mm, although it depends on the output intensity of the near infrared ray emission source.

For example, the second filter 16b absorbs a wavelength of less than 1100 nm with a light absorbing material dispersed in glass, and transmits a wavelength of 1100 nm or more to the living body 2 side. The filter 16b may be, for example, a commercially available near-infrared filter, or a composite filter in which the filter 16b is combined with an ultraviolet filter. More specifically, the near infrared filter includes a dielectric film coating filter, an optical glass filter, and a resin filter. Dielectric film coating filters are made by alternately stacking multiple layers of metal oxides and metal fluorides with different refractive indexes, and select light in the near-infrared wavelength region of less than 1100 nm using light interference by transparent thin films. For example, a dielectric multilayer film such as a laminated film of a high refractive index layer such as vapor deposited TiO ₂ and a low refractive index layer such as vapor deposited SiO ₂ is formed on a transparent substrate such as a glass substrate. And a dielectric multilayer coating filter attached thereto. The optical glass filter is CuO-fluorophosphate glass containing 0.5% or less of V ₂ O ₅ and metal fluoride in the main components P ₂ O ₅ and CuO, and the resin filter is a diimonium dye. And a resin film containing 50% or less of a near-infrared absorbing dye. A combination of a plurality of ultraviolet shielding filters / infrared shielding filters having different cutoff wavelengths, a filter infrared transmission filter, and a cold filter may be used as long as the wavelength is less than 1100 nm. It is preferable that the wavelength range of the near infrared rays irradiated is 1000-1800 nm, and it is still more preferable in it being 1000-1700 nm or 1100-1800 nm.

  A laser diode 15, filters 16 a and 16 b, and a lens 17 that are arranged side by side and coolers 19 a and 19 b that are arranged along the laser diode 15 are arranged in the housing of the handpiece 30 that the operator has. A sapphire glass cooling window 18 is attached to the front end surface of the handpiece 30 and is exposed so that it can come into contact with the living body 2.

  The coolers 19a and 19b are water-cooled coolers, air-cooled coolers, heat exchange coolers using rectifiers or thyristor converters, thermoelectric conversion elements, and the heat accumulated in the first filter 16a and the sapphire glass cooling window 18. Are to be released.

  An oscillation circuit 11 is connected to the modulation circuit 13 for emitting laser light in pulses, and is further connected to a laser diode 15 in the handpiece 30 via a connection cord. A timer 12 that emits laser light continuously for a predetermined time and a switch circuit 14 that emits the laser light once or a plurality of times are connected to the modulation circuit 13. Further, a cooler control circuit 21 is connected to the coolers 19 a and 19 b in the handpiece 30. These circuits 11, 13, 14, 21 and the timer 12 are built in the housing of the controller main body 40 of the tumor treatment apparatus 1.

  A near-infrared reflector (not shown) may be provided on the back side of the laser diode 15. Instead of the laser diode 15, an AlGaAs-based or GaAs-based light emitting diode may be used.

  The tumor treatment device 1 is used as follows.

For each irradiation treatment, the oscillation from the oscillation circuit 11 is emitted by the timer 12 and the modulation circuit 13 emits a near infrared pulse with a pulse width of 0.5 to 100 milliseconds, for example, at intervals of 0.5 to 100 milliseconds. And / or modulation by the switch circuit 14 so as to be a single shot continuous for 0.1 to 10 seconds per shot or a multiple shot of 2 to 20 times per shot, and an amplifier circuit ( Via a not-shown voltage, a voltage that gives a desired output power of 5 to 65 J / cm ^2, preferably 5 to 56 J / cm ² is applied to the laser diode 15. This irradiation treatment is repeatedly performed every day or at regular intervals.

  Then, laser light including near infrared rays having a wide range of wavelengths is pulsed from the laser diode 15 serving as a flash lamp. Those in unnecessary wavelength bands are reduced or shielded by the filters 16a and 16b. That is, the near-infrared rays reach the first filter 16a, and a part of the wavelength of 1400 to 1500 nm is absorbed in the water layer in the filter 16a. As a result, the transmission of the wavelength is reduced, and most wavelengths exceeding 1800 nm are obtained. As a result of absorption, transmission at that wavelength is blocked. At this time, the first filter 16a is cooled by the cooler 19a driven according to the instruction signal from the cooler control circuit 21, and as a result, the water layer in the first filter 16a whose water temperature rises due to absorption of near infrared rays is also cooled at the same time. . Further, the laser light reaches the second filter 16b, and the wavelength of less than 1100 nm is almost absorbed. As a result, the transmission of the wavelength is almost blocked. The laser light is focused by the lens 17 as necessary, passes through the sapphire glass cooling window 18, becomes a near infrared ray 20 having a desired wavelength to be irradiated, and is emitted to the outside.

  The sapphire glass cooling window 18 at the tip of the handpiece 30 is brought into contact with the skin of the living body 2 toward the tumor tissue 3 of the living body 2 to be treated. Then, the near infrared ray 20 reaches the tumor tissue 3 through the skin and dermis of the skin in the living body 2. At this time, moisture in the skin is heated by the near-infrared rays 20, but because the epidermis is in contact with the sapphire glass cooling window 18, the heat of the epidermis and dermis is transferred to the sapphire of the cooling window 18 having high thermal conductivity. Conduct. The sapphire glass cooling window 18 is cooled to a constant temperature of, for example, 20 ° C. by a cooler 19b driven according to an instruction signal from the cooler control circuit 21, so that no adverse events such as heat, burns, and pain occur. Always cool the epidermis and dermis.

  The near-infrared rays 20 reach the tumor tissue 3 safely without causing adverse events such as heat, burns, and pain, and are not absorbed by the surface, and destroy the tumor cells. In healthy tissue, the near infrared ray 20 does not cause thermal denaturation of proteins and the like, and is protected from excessive temperature rise with abundant blood flow. On the other hand, since cells in the growth phase of the malignant tumor tissue 3 such as tumor cells and tumor foci are highly sensitive to the near infrared ray 20, the energy of the near infrared ray 20 is absorbed by the malignant tumor tissue 3 more. As a result, spontaneous death of the malignant tumor tissue 3 can be induced and tumor treatment can be performed.

  FIG. 2 shows another aspect of the tumor treatment apparatus 1. The near-infrared emission source 15 may emit a wavelength region from ultraviolet rays and visible light as long as it is infrared rays including near infrared rays of 1100 to 1800 nm. Therefore, as shown in FIG. Instead, a lamp that emits near-infrared rays, for example, a tungsten lamp that is a white light bulb with tungsten as a filament, a halogen lamp that contains a tungsten wire with a tungsten filament, and a discharge lamp that contains xenon gas. A xenon lamp may be used. The first filter 16a that absorbs a wavelength of 1400 to 1500 nm in the near-infrared ray is configured to put water into the gap 23 of a cell made of a transparent inorganic material such as quartz or glass, or a transparent resin such as an epoxy resin or a silicone resin. It may be allowed to pass through. The order of the filters 16a and 16b may be reversed.

  The tumor treatment apparatus 1 of FIG. 2 operates as follows. A wide range of wavelengths of light emitted from the tungsten lamp 15 serving as a flash lamp or reflected by the reflector 22 is pulsed. The light beam reaches the first filter 16a, and a part of the light is absorbed by the water in the gap 23 of the cell of the filter 16a to reduce the transmission of the wavelength of 1400 to 1500 nm and cut off the transmission of the wavelength exceeding 1800 nm. . A pump (not shown) is driven in accordance with an instruction signal from the cooler control circuit 21 (see FIG. 1), the water in the gap 23 is circulated, and the filter 16a is cooled. Further, the light beam reaches the second filter 16b, and transmission of light having a wavelength of less than 1100 nm is almost blocked. The light beam is appropriately focused by the lens 17, passes through the sapphire glass cooling window 18, becomes a near infrared ray 20 having a desired wavelength to be irradiated, and is emitted to the tumor tissue 3 in the living body 2.

  FIG. 3 shows another aspect of the tumor treatment apparatus 1. As shown in FIG. 3, the near-infrared radiation source 15 is a heater that emits heat rays including near-infrared rays, for example, a carbon heater that uses carbon fiber as a heat source, and heats insulating ceramics in place of the laser diode. It may be a ceramic heater that uses a radiation source or a semiconductor ceramic as a heat source. The first filter 16a that absorbs a wavelength of 1400 to 1500 nm in the near infrared is composed of a transparent inner tube made of quartz or glass into which these rod-shaped heaters are inserted, and quartz, glass, or epoxy into which they are inserted. It may be formed of a double pipe 24 made of a resin outer pipe such as resin or silicone resin, and water flowing through a gap 23 between the inner pipe and the outer pipe. The heater 15 does not have to have an oscillation circuit or a modulation circuit in order to continuously emit heat rays, and may instead have an amplifier circuit. May be provided with a shutter (not shown).

  The tumor treatment apparatus 1 in FIG. 3 operates as follows. A voltage that provides a desired output is applied to the heater 15 via the amplifier circuit (not shown) by the timer 12 or the switch circuit 14 (see FIG. 1). The heat rays emitted from the heater 15 reach the first filter 16a that surrounds the heat ray, and a part of the heat rays is absorbed by the water in the gap 23 between the double tubes 24 of the filter 16a, and the wavelength of 1400 to 1500 nm. Transmission is reduced, and transmission of wavelengths exceeding 1800 nm is blocked. A pump (not shown) is driven according to an instruction signal from the cooler control circuit 21 (see FIG. 1) to circulate water in the gap 23, and the heater 15 is cooled together with the filter 16a. The heat rays that have passed through the filter 16a are reflected directly or by the reflecting plate 22 to reach the second filter 16b, and transmission of wavelengths less than 1100 nm is almost blocked. The heat rays are appropriately focused by the lens 17, passed through the sapphire glass cooling window 18, become near infrared rays 20 having a desired wavelength to be irradiated, and are irradiated to the tumor tissue 3 in the living body 2.

  FIG. 4 shows one aspect of the handpiece 30 of the tumor treatment device 1. As shown in FIG. 4, a first tubular filter 16 a (see FIG. 2) is built in the housing 31 of the handpiece 30. A near infrared ray emission source 15 is inserted into the filter 16a. Water circulates between the filter 16a and the near infrared radiation source 15. The housing 31 may be provided with a switch 32 that controls on / off of irradiation, and may be connected to the switch circuit 14 (see FIG. 1). When the switch 32 is set to the on mode, the laser light from the near-infrared emission source 15 is emitted, and the near-infrared ray 20 is irradiated through the sapphire glass cooling window 18. The on / off control may be performed on the controller body 40 side.

  FIG. 4 shows an example in which a pair of the near-infrared radiation source 15 and the filter 16a is provided. However, a pair of each of the plurality of handpieces 30 may be provided. A plurality of pairs may be provided in each of 30.

  Although the tumor treatment apparatus 1 has shown an example of irradiating the skin with near-infrared rays so that the near-infrared rays reach the tumor tissue in the deep part of the skin, the near-infrared radiation source inserted in the inner space near the tip of the catheter and the near-infrared emission source are covered. It may have a filter and may be combined with an endoscope. The near infrared ray from the near infrared emitting source may be photoconductive to the vicinity of the filter by an optical fiber. This makes it possible to irradiate an organ deeper than the skin, such as the brain and internal organs.

  The tumor treatment device 1 is not limited in the pulse width and pulse interval of shots, but may be one that performs multiple shots with a desired constant pulse width and a desired constant pulse interval by a modulation circuit. The pulse width and the pulse interval may be increased or decreased in the middle.

  Although the tumor treatment apparatus 1 has shown an example in which the sapphire glass cooling window 18 is water-cooled, it may be air-cooled.

  Although the example which is used for the human malignant tumor was shown, the tumor treatment apparatus 1 may be used for a human benign tumor or may be used for a malignant tumor / benign tumor of a non-human animal such as a pet. The tumor tissue of these malignant tumors / benign tumors may be used for residual tumor tissues that could not be removed when surgery was performed and normal tissues around it. It may be used in combination with other therapies such as chemotherapy or X-ray irradiation therapy.

  According to these tumor treatment apparatuses 1, the wavelength of the near infrared ray 20 irradiated to the tumor tissue can be limited to 1000 to 1800 nm, preferably 1000 to 1700 nm or 1100 to 1800 nm.

  Those having a wavelength of less than 1100 nm, particularly less than 1000 nm, are less likely to reach the tumor tissue deeper than the epidermis in the living body due to the short wavelength, and are absorbed by the skin surface due to the higher energy. It causes radiation and other adverse events in the dermis, so it is not irradiated. In addition, those having a wavelength of less than 1100 nm, particularly less than 1000 nm are absorbed at a very high rate by melanin on the surface of the skin, and pigmented skin having a large amount of melanin or even white race is pigmented. Irradiation to skin with colored parts such as areola, nipple, pubic area, etc. causes severe adverse events such as severe pain and burns, so it is not irradiated.

  Even if the wavelength exceeding 1800 nm reaches the tumor tissue deeper than the epidermis in the living body to heat the tumor tissue, the amount of energy suppresses the growth of malignant tumor cells and suppresses the malignant tumor. Because it is insufficient to treat, it is not irradiated.

  On the other hand, near infrared rays having a wavelength of 1400 to 1500 nm are absorbed at a very high rate by hemoglobin and water in the living body. For that reason, when near-infrared rays of that wavelength are irradiated to sites with a lot of hemoglobin, such as reddish skin, inflammation, and mucous membranes, they are absorbed particularly at those sites, causing adverse events such as burns. . In addition, when a near infrared ray of that wavelength is irradiated to some skin, it is absorbed at a high rate by the moisture of the dermis, causing strong pain. Therefore, the near infrared ray of that wavelength is not irradiated. As described above, near infrared rays are absorbed at a high rate at a portion where there is a large amount of hemoglobin and water, and thus it is difficult to reach the deep tissue.

  As described above, since the tumor treatment apparatus 1 is designed so that near infrared light having a wavelength of 1400 to 1500 nm can be cut with a special filter, it is possible to irradiate a portion having a lot of hemoglobin or melanin with the near infrared light, It has become possible to attenuate pain more, to reduce adverse events, and to reach deep tissue with sufficient near infrared rays.

  Hereinafter, examples using a tumor treatment apparatus to which the present invention is applied will be described.

  The tumor treatment apparatus was used to measure the growth inhibition of tumor cells when near-infrared rays were irradiated to the in vitro tumor cells. A specific method is as follows.

Example 1
As tumor tissues, rat melanoma B16F0, human gastric cancer cell NUGC4, human breast cancer cell MCF7, and human uterine cancer cell Hela were used. These were cultured at 5 × 10 ³ cells / well in a humidified 37 ° C. incubator containing 5% CO ₂ in a commercial medium in the wells of the culture dish. As a tumor treatment device for irradiating tumor cells with near-infrared rays in the wavelength range 1000-1800 nm with the wavelength range 1400-1500 nm reduced, it is rejuvenated in plastic surgery and dermatology. Titan (trade name, manufactured by Kütera) used for treatment was used. Each tumor cell was irradiated with near-infrared rays by this tumor treatment apparatus. Irradiation conditions, the output intensity of 20 J / cm ² or 40J / cm ^2, 20J / when cm ² 2.3 sec, and 1 shot single pulse of 4.17 seconds when 40 J / cm ² 3 times, 10 Multiple or 20 shots were repeated. In addition, the intensity of 20 J / cm ² by this treatment device is such an output that a healthy person does not feel anything even when irradiated to the skin because of the cooler, and the intensity of 40 J / cm ² is that the healthy person applies to the skin. The output is such that it feels slightly warm when irradiated, or slightly hot for an instant depending on the individual. Further, in order to prevent excessive temperature rise and eliminate the possibility of tumor cell damage due to accumulated heat based on the excessive temperature, the temperature of the bottom of the medium in each well is measured for each shot, and the medium temperature is 37 ° C. We waited until we got back to the next shot.

When measuring the degree of growth of tumor cells, it is as follows.
The first group was measured after culturing for 3 days after irradiation of the first multiple shots.
The second group was measured after culturing for 6 days after irradiation of the first multiple shots.
The third group was measured after culturing for 3 days after irradiation of the first multiple shots, and after culturing for 3 days after further irradiation of the second multiple shots.
The fourth group was measured after culturing for 3 days after irradiation of the first multiple shots, and after culturing for 6 days after irradiation of the second multiple shots.
The control group was measured without irradiation.

A specific method for measuring the proliferation of tumor cells is to use a tetrazolium salt MTS (3- (4,5-dimethylthiazol-2-yl) as an index of tumor cell viability by dehydrogenase in mitochondria in the tumor cells. ) -5- (3-carboxymethoxyphenyl) -2- (4-sulfophenyl) -2H-tetrazolium, inner salt) produced by reduction of Formazan, CellTiter 96 Aqueous Cell Proliferation Assay kit (Promega Corporation) Product), the absorbance at 490 nm (OD ₄₉₀ ) is measured. The results for the absorbance corresponding to the number of surviving tumor cells (surviving number) are shown in FIGS. * In the figure indicates that there is a statistically significant difference (P <0.05) by Student's t test.

  As is apparent from FIGS. 5 and 6, in vitro experiments were performed by infra-red irradiation using a tumor treatment apparatus, rat melanoma B16F0, human gastric cancer cell NUGC4, human breast cancer cell MCF7, human uterine cancer cell Hela. Was able to dramatically reduce the survival rate.

  This is because the survival rate of all malignant tumor cells is significantly reduced by the near infrared irradiation using the tumor treatment apparatus of the present invention, and the near infrared irradiation suppresses the growth or kills the malignant tumor cells. Is shown. From this, it was revealed that this tumor treatment apparatus is extremely effective for treating malignant tumors.

  Moreover, the specific measurement method of the culture medium temperature of each well is the digital thermometer MC3000-000 (product of Chino Co., Ltd.) equipped with a thermocouple for each group. First, it measures.

The average temperature of the medium rose from 37 ° C. to 40.8 ° C. in the case of 20 J / cm ² shot, increased to 40 ° C. or higher for 3.6 seconds, and then returned to the original temperature after 43.8 seconds. In addition, in the case of 40 J / cm ² shot, the temperature rose from 37 ° C. to 43.9 ° C., became 40 ° C. or higher for 42.1 seconds, and then returned to the original temperature after 83.4 seconds. In the case of hyperthermia for tumors of cancer patients, the tumor tissue does not decrease dramatically even after heating for a long time at about 42 ° C for about 60 minutes, or even if the cancer patients have a high temperature due to a cold, etc. Since the tumor tissue does not shrink and the cancer cells do not decrease even when exposed to 40 to 44 ° C. for 1 to 2 minutes in vitro, the near-infrared radiation irradiated from this tumor treatment device is directly related to thermal energy. It is speculated that the growth of malignant tumor cells is directly suppressed regardless of the relationship.

  Next, tumor cell growth suppression when in vivo tumor tissue was irradiated with near infrared rays was examined using a tumor treatment apparatus. The specific method is to measure the volume of the tumor tissue and observe the tumor tissue specimen pathologically as follows.

(Example 2)
A tumor cell of human breast cancer cell MCF7 was used as a tumor tissue, and a female SCID mouse (Charles River Japan, strain CB17 / Icr-Prkdcsid / CrlCrlj) was used as an in vivo transplantation experimental animal.
Human breast cancer cell MCF7 was a commercially available medium and cultured in a humidified 37 ° C. culture apparatus containing 5% CO ₂ . Cultured MCF7 cells in the exponential growth phase were adjusted to 2.5 × 10 ⁶ cells / 100 μL / individual to obtain tumor cells for transplantation. This SCID mouse of 6 weeks of age was used as an irradiation group, and tumor cells of human breast cancer cells MCF7 were transplanted subcutaneously on the right side of the trunk of each of five mice. After transplantation, the mice were bred to grow tumor tissue. When the average tumor tissue volume reached 66 mm ³ , if the tumor tissue had hair, the hair was removed with a hair removal cream. 4 and 4 were irradiated with near-infrared rays having a wavelength range of 1000 to 1800 nm in which the wavelength range of 1400 to 1500 nm was reduced without anesthesia. Irradiation conditions were 20 J / cm ² output intensity, and a single shot of 2.3 seconds was repeated 10 times as a single shot, with multiple shots taken as 1 cool, the first day, 2, 4, 6, 8, 9, 10th day A total of 7 cool irradiations were performed. At the time of the near-infrared irradiation, none of the SCID mice moved finely even without anesthesia, so it seemed that no pain or heat was felt. In addition, no side effects such as redness, erythema, swelling and burns were observed in the vicinity of the near infrared irradiation site.

In order to investigate the tumor suppressive effect of the tumor treatment device, the major axis, minor axis, and thickness of the tumor tissue are measured at any time, and the following formula (1)
Tumor tissue volume (mm ³ ) = (4/3) × π × (L / 2) × (W / 2) × (T / 2) (1)
(Wherein, L is the tumor tissue major axis (mm), W is the tumor tissue minor axis (mm), and T is the tumor tissue thickness (mm)).
From the above, the tumor tissue volume was calculated. The result is shown in FIG. In FIG. 7, * indicates a statistically significant difference of P <0.05, and ** indicates a significant difference of P <0.01.

  Further, on the 13th and 37th days, a tumor tissue was excised from one of the irradiated groups, cut into 3 sections, and stained with hematoxylin and eosin (HE) and transferase for detecting and detecting apoptotic cells, respectively. Mediating dUTP nick end labeling (TUNEL) staining and immunostaining for Ki67 specifically present in tumor cells as proliferating cells were performed, and histopathological observation was performed with an optical microscope. The results are shown in FIGS.

(Comparative Example 1)
Except not performing near-infrared irradiation, in the same manner as in Example 2, using five SCID mice in the control group, the tumor tissue was measured for the major axis, minor axis, and thickness of the tumor tissue as needed. Tissue volume was calculated and histopathological observation was performed. The results are shown in FIGS.

  As is clear from FIG. 7, the non-irradiated control group of Comparative Example 1 showed a rapid increase in tumor tissue volume with the elapsed days, especially after the seventh day. In the irradiated group of Example 2, near-infrared irradiation By repeating the above, the tumor tissue volume decreased significantly and steadily immediately after the near-infrared irradiation on the first day, and remained for a while even after the near-infrared irradiation was stopped on the 10th day.

  Further, as is apparent from FIG. 8, on the 10th day of the last day of near-infrared irradiation, in the irradiation group, the tumor tissue was reduced as in the HE staining result as compared with the control group, and as in the TUNEL staining result. In contrast, the number of apoptotic cells stained in a markedly increased amount, and the number of tumor cells that proliferated and stained as in the immunostaining results of Ki67 were remarkably reduced.

  Furthermore, as is apparent from FIG. 9, on the 37th day after the near-infrared irradiation was stopped, the tumor tissue remained reduced as in the HE staining result, and the apoptotic cells stained as in the TUNEL staining result The number of tumor cells increased significantly in the central part of the tumor tissue, and the number of tumor cells that proliferated and stained as in the immunostaining result of Ki67 significantly decreased in the central part of the tumor tissue.

  From the comparison between Example 2 and Comparative Example 1, a statistically significant difference was observed, and the proliferation of tumor cells such as human breast cancer cell MCF7 was observed by irradiation with near infrared rays using this tumor treatment apparatus. It was shown that it can be suppressed dramatically and reliably.

(Example 3)
As tumor tissue, mouse melanoma cell MDA-MB-435 tumor cells were used, and in vivo transplantation experimental animals were female nude mice (manufactured by Charles River Japan, strain Crlj: CD1-Foxn1 ^nu (ICR Nude mice)) were used.
Tumor cells of mouse melanoma cells MDA-MB-435 were cultured in a humidified 37 ° C. culture apparatus containing 5% CO ₂ with a commercially available medium. Cultured MDA-MB-435 cells in the exponential growth phase were adjusted to 5.0 × 10 ⁶ cells / 100 μL / individual to obtain tumor cells for transplantation. This nude mouse of 6 weeks of age was used as an irradiation group, and tumor cells of mouse melanoma cells MDA-MB-435 were implanted subcutaneously on the right side of the trunk of 20 mice. After transplantation, mice were bred, tumor tissue was grown, and when the average tumor tissue volume reached 100 mm ³ , 14 mice were selected so that the tumor tissue volume was uniform, and described in FIGS. The tumor site was irradiated with near-infrared rays having a wavelength range of 1000 to 1800 nm in which the wavelength range of 1400 to 1500 nm was reduced with Titan (manufactured by Cutera; trade name) without anesthesia. Irradiation conditions were 20 J / cm ^{2 with} an output intensity of 2.3 seconds. One shot was repeated 10 times with a single pulse of 2.3 seconds, and a total of 13 cool irradiations from the first day to the 13th day. After stopping the irradiation, a total of 13 cool irradiations were resumed from the 31st day to the 43rd day in a row. At the time of the near-infrared irradiation, none of the ICR nude mice moved finely even under no anesthesia, and no pain or heat was felt, and there were no side effects such as epithelial burns near the near-infrared irradiation site. There wasn't.

  In order to examine the tumor suppression effect of the tumor treatment apparatus, the major axis, minor axis, and thickness of the tumor tissue were measured as needed, and the above-described equation (1) tumor tissue volume was calculated. The result is shown in FIG. In FIG. 10, * indicates a statistically significant difference of P <0.05, and ** indicates a statistically significant difference of P <0.01.

  In addition, on day 9 and 45, tumor tissue was excised from one of the irradiated groups, cut into 3 sections, each subjected to HE staining, TUNEL staining, and Ki67 immunostaining, and pathological examination was performed using an optical microscope. Histological observations were made. The results are shown in FIGS.

(Comparative Example 2)
Except not performing near-infrared irradiation, in the same manner as in Example 3, 14 nude mice in the control group were used, and the tumor tissue was measured for the major axis, minor axis and thickness of the tumor tissue as needed. Tissue volume was calculated and histopathological observation was performed. The results are shown in FIGS.

  As is clear from FIG. 10, in the non-irradiated control group of Comparative Example 2, the tumor tissue volume increased with the elapsed days, but in the irradiation group of Example 3, by repeating near-infrared irradiation until the 13th day, Immediately after the near-infrared irradiation on the first day, the tumor tissue volume decreased significantly and steadily decreased even after the near-infrared irradiation was stopped. Thereafter, the tumor tissue volume started to increase, but when near-infrared irradiation was resumed from the 31st day, the tumor tissue volume decreased significantly and steadily again. Usually, in the chemotherapy or hyperthermia treatment for cancer patients, once the tumor tissue has acquired anticancer drug resistance or heat resistance, the therapeutic effect is no longer recognized by the same therapy. However, this tumor treatment device has a feature that even if the tumor reappears after irradiating the tumor tissue with near infrared rays, if the tumor tissue reappears again, the tumor tissue can be reduced or killed if it starts irradiating near infrared rays again. Indicated.

  In addition, as is clear from FIG. 11, on the ninth day in the middle of near-infrared irradiation every day, the irradiated group had a tumor tissue reduced as in the HE staining result as compared with the control group, and the TUNEL staining result. As shown in the results of Ki67 immunostaining, the number of proliferating and stained tumor cells was remarkably reduced.

  Further, as clearly shown in FIG. 12, on the 45th day after the resumed near-infrared irradiation was stopped, the tumor tissue remained reduced as in the HE staining result, and the apoptotic cells stained as in the TUNEL staining result However, the number of tumor cells that proliferated and stained as shown in the results of Ki67 immunostaining was significantly reduced in the center of the tumor tissue.

  From the comparison between Example 3 and Comparative Example 2, a statistically significant difference was observed. By irradiation with near infrared rays using this tumor treatment apparatus, tumor cells such as human melanoma cells MDA-MB435 were observed. It has been shown that proliferation can be suppressed dramatically and reliably.

  Thus, it is clear that the tumor treatment apparatus of the embodiment to which the present invention is applied reduces or kills various tumor tissues with near infrared rays. Although the mechanism is not necessarily clear, it is guessed as follows. FIG. 13 shows the correlation between the wavelength of 400 to about 3000 nm, the irradiance when this tumor treatment apparatus is used, and the absorption coefficients of melanin, hemoglobin, and water. As shown in FIG. 13, the near infrared ray emitted from the tumor treatment apparatus has a high irradiance particularly in the wavelength range of 1000 to 1800 nm, and among them, the irradiance is particularly low in the wavelength range of 1400 to 1500 nm. Near-infrared radiation can also be applied to sites with a lot of melanin. Near-infrared light having a reduced intensity in the wavelength range of 1400 to 1500 nm irradiated by this tumor treatment device has increased permeability to the skin and its deep part. Directly acting on tumor cells, the decrease or disappearance of tumor tissue is caused to induce cell death due to DNA destruction or apoptosis in a manner independent of thermal energy. Thus, it seems that the mechanism of tumor tissue reduction is completely different from hyperthermia, in which a sensitizer is administered to tumor tissue and infrared rays are irradiated to the tumor tissue in order to accumulate thermal energy.

  Moreover, since the surface was cooled to 20 ° C. in the tumor treatment apparatus used in Examples 1, 2, and 3, near infrared rays reached the deep part and the center part of the tumor without absorbing near infrared rays on the tumor surface, and the tumor The cells could be reduced or killed. The stronger the degree of cooling, the near infrared rays can be delivered to the deep part, and the tumor existing in the deeper part can be reduced or killed. Furthermore, in Examples 1, 2, and 3, the degree of damage to the tumor on the surface layer is mild, but if the surface cooling is weakened, near-infrared rays are absorbed by the tumor on the surface layer, and the tumor is reduced or killed. be able to. This temperature control makes it possible to treat tumors present at various depths.

  The tumor treatment apparatus of the present invention can be used for the treatment of benign or malignant tumors of humans and non-human animals, particularly malignant tumors that can be made into organisms such as skin cancer and breast cancer, and proliferative diseases such as leukemia.

The present invention relates to a device used for the purpose of irradiating a tumor tissue of a human or non-human animal, particularly a malignant tumor lesion, with near-infrared rays to cause the tumor to spontaneously die for treatment.

The tumor tissue cell death induction device for tumor treatment according to claim 1, which has been made to achieve the above object, absorbs a wavelength of 1400 to 1500 nm in the emitted light from the near-infrared ray emission source. In addition, a filter that reflects or scatters and transmits near-infrared rays is disposed in the middle of the path between the near-infrared emission source and the tumor tissue of the living body irradiated with the near-infrared rays, and the near-infrared wavelength region is A cooling window that contacts the living body is disposed at the tip of the filter in the middle of the path, and a cooling device is attached to the cooling window. A single pulse with an output intensity of 65 J / cm ² is taken as one shot, and a modulation circuit for driving the near-infrared radiation source is provided so that it is irradiated with a single shot or multiple shots. The near-infrared irradiation energy that directly inhibits and / or kills tumor cells of the tumor tissue by irradiation of the near-infrared surface of the tumor tissue and / or the deep part of the tumor tissue that has passed through the filter without depending on thermal energy. It is characterized by being adjusted to .

The tumor tissue cell death inducing apparatus for tumor treatment according to claim 2 is the one described in claim 1,
The modulation circuit modulates the single pulse having a pulse width of 0.5 to 100 milliseconds so that near infrared pulses are emitted at intervals of 0.5 to 100 milliseconds, and / or 0. Modulation is performed so that the single shot is continuous for 1 to 10 seconds or the multiple shots are 2 to 20 times .

The tumor tissue cell death induction apparatus for tumor treatment according to claim 3 is the one described in claim 1, wherein the modulation circuit uses the single pulse with an output intensity of 20 J / cm ^{2 as} the near infrared ray , The shot is irradiated at least 10 times, or the shot is irradiated at least 3 times with the single pulse having an output intensity of 40 J / cm ² .

The tumor tissue cell death induction apparatus for tumor treatment according to claim 4 is the one described in claim 1, wherein the cooler cools the cooling window to 20 ° C.

The tumor tissue cell death induction apparatus for tumor treatment according to claim 5 is the apparatus described in claim 1, wherein the filter has an aqueous layer .

The tumor tissue cell death induction apparatus for tumor treatment according to claim 6 is the one described in claim 1, wherein the near-infrared emission source emits a laser beam as the emission beam, or the emission It is a light emitting diode that emits light, a tungsten lamp, a halogen lamp, a xenon lamp, a carbon heater, or a ceramic heater.

The tumor tissue cell death inducing apparatus for tumor treatment according to claim 7 is the apparatus described in claim 1 ,
Connected to the modulation circuit is an oscillation circuit that emits the emitted light in pulses, a timer that emits the emitted light continuously for a predetermined time, and a switch circuit that emits the emitted light one or more times repeatedly It is characterized by being.

The tumor tissue cell death inducing apparatus for tumor treatment according to claim 8 is the one described in claim 1 ,
One or more pairs of the near-infrared ray emission source and the filter are provided.

The tumor tissue cell death induction apparatus for tumor treatment according to claim 9 is the one described in claim 8 , wherein the pair of the near-infrared ray emission source and the filter is each tip of one or a plurality of handpieces. It is characterized by being attached to .

The tumor tissue cell death induction apparatus for tumor treatment according to claim 10 is the one described in claim 9 , wherein the cooling window is exposed and attached to the surface of the handpiece. .
The tumor tissue cell death induction apparatus for tumor treatment according to claim 11 is the one described in claim 1, wherein the near region inserted into the inner space of the tip of a catheter inserted into the body of a human or non-human animal. The infrared radiation source is covered with the filter.
The tumor tissue cell death induction apparatus for tumor treatment according to claim 12 is the tumor tissue cell death induction apparatus according to claim 1, wherein the tumor tissue of the living body is a malignant tumor and / or a benign tumor of a human or non-human animal. It is characterized by.

Claims (10)

  A filter that absorbs, reflects, or scatters the wavelength of 1400-1500 nm of the emitted light from the near-infrared ray emission source and transmits the near-infrared ray, the near-infrared ray emission source, and the tumor tissue of the living body irradiated with the near-infrared ray A tumor treatment apparatus, which is arranged in the middle of the path.   The tumor treatment apparatus according to claim 1, wherein the filter has an aqueous layer.   2. The tumor treatment apparatus according to claim 1, wherein the near infrared wavelength range is 1000 to 1800 nm.   The near-infrared radiation source is a laser diode that emits laser light that is the emitted light, or a light-emitting diode that emits the emitted light, a tungsten lamp, a halogen lamp, a xenon lamp, a carbon heater, or a ceramic heater. The tumor treatment device according to claim 1.   The near-infrared radiation source is an oscillation circuit for pulsed emission of the emitted light or an emission circuit for continuous emission, a timer for emitting a single shot or multiple shots of the emitted light, and a switch circuit for starting and stopping the emission. And / or an amplifying circuit for amplifying an output of the near-infrared ray emission source.   The tumor treatment apparatus according to claim 1, comprising a pair or a plurality of pairs of the near-infrared radiation source and the filter.   The tumor treatment apparatus according to claim 6, wherein a pair of the near-infrared radiation source and the filter is attached to each distal end portion of one or a plurality of hand pieces.   The tumor treatment apparatus according to claim 7, wherein a sapphire glass cooling window that comes into contact with the living body is exposed and attached to the surface of the handpiece in front of the filter in the middle of the path.   The tumor treatment apparatus according to claim 1, wherein the filter covers the near-infrared emission source inserted in the inner space of the tip of a catheter inserted into the body of a human or non-human animal.   The tumor treatment apparatus according to claim 1, wherein the tumor tissue of the living body is a malignant tumor and / or a benign tumor of a human or non-human animal.

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