RU2482891C2 - Radio-frequency hyperthermia apparatus with targeted feedback modulation - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: group of inventions refers to a radio-frequency apparatus and a method for capacitively coupled hyperthermia. The apparatus comprises a radio-frequency source, an amplifier, a sensor, a feedback amplifier, and a modulation signal generator, wherein the radio-frequency source generates a source signal which is modulated by the modulation signal generator, amplified by the amplifier and directed to a target. The sensor receives a feedback signal from the target that is directed to the feedback amplifier, wherein the feedback signal is amplified by the feedback amplifier and modulates the source signal to generate a target-modified signal.

EFFECT: group of inventions allows higher selectivity in treating hyperthermia.

13 cl, 6 ex, 28 dwg

Description

The present invention relates to a radio frequency (RF) device for hyperthermia comprising a radio frequency source, an amplifier, a sensor, an optional feedback amplifier and a modulating signal generator, where the radio frequency source generates a source signal that is modulated by a modulating signal generator, amplified by an amplifier, and directed to a target , the sensor receives the feedback signal from the target, which is sent to the feedback amplifier, where, if necessary, amplifying the feedback signal they are powered by a feedback amplifier and the source signal is modulated to generate a signal modified by the target. This radiofrequency (RF) device for hyperthermia is intended to increase the selectivity of hyperthermia treatment.

State of the art

Heating is widely used in many fields of medicine, and is also used for cosmetic effects. For example, radiofrequency / microwave hyperthermia devices can be used to enhance energy absorption in tissue to cause damage to unwanted structures and / or raise the temperature of the target area above normal body temperature. One application for hyperthermia devices is in the treatment of a malignant tumor.

With hyperthermia, the problem of selectivity remains, since it is desirable to selectively heat the target tissue / cell in order to destroy or contribute to the destruction of the target tissue / cell while minimizing damage to healthy tissue.

Therefore, there remains a need to provide more selective treatment for hyperthermia in order to increase the effectiveness of the treatment of malignant tumors and the treatment of other diseases.

Thus, the aim of the present invention is to provide a radio frequency device for the selective treatment of hyperthermia, in particular malignant tumors and proliferative diseases, as well as pain.

This goal is achieved through the independent claims. Additional favorable features and embodiments obviously follow from the description, examples and dependent claims.

SUMMARY OF THE INVENTION

The present invention relates to a radio frequency device for hyperthermia for capacitor coupling and without a dipole antenna, comprising a radio frequency source (1), an amplifier (2), a sensor (3) and a modulating signal generator (13), where the radio frequency source generates a source signal (8), which is modulated by a modulating signal generator (13) to generate a modulated source signal (10), the modulated source signal (10) is amplified by an amplifier (2) and sent to the target (17), and the sensor receives a feedback signal ides (5) from the target, where the feedback signal (5) modulates the source signal (8) to generate a modulated signal (4) modified by the target.

In the event that it is necessary to amplify the feedback signal (5), in the proposed device, you can use the feedback amplifier (6) to amplify the feedback signal (5).

In the event that a feedback amplifier (6) is present, the present invention relates to a radio-frequency device for hyperthermia for capacitor coupling and without a dipole antenna, which comprises a radio frequency source (1), an amplifier (2), a sensor (3), a feedback amplifier ( 6) and a modulating signal generator (13), where the radio frequency source generates a source signal (8), which is modulated by a modulating signal generator to generate a modulated source signal (10), I amplify the modulated source signal (10) through the amplifier and sent to the target (17), and the sensor receives the feedback signal (5) from the target, which is sent to the feedback amplifier (6), where the feedback signal is amplified by the feedback amplifier (6), and it modulates the source signal to generate a modulated target modulated signal (4).

You can also combine the functions of two or more parts of the proposed device for hyperthermia. For example, the modulating signal generator (13) and the feedback amplifier (6) can be combined so that amplification and modulation are performed by one part of the device. In this case, the modulating signal generator (13) can also amplify the feedback signal (5) and can also modulate the feedback signal (5) in order to generate a modulating signal (12).

The proposed device for hyperthermia uses a capacitor coupling between the electrodes and the RF current, which also passes through the target tissue of the patient, while the part of the patient’s body between the electrodes acts as a dielectric material, where the target tissue is heated by the Joule heat (Q = I ² R) generated by converting the flowing current through the target tissue into heat, and also by means of the potential difference used to manifest the effect of the electric field. The selectivity for heat generation mainly within the target tissue or diseased tissue, but not in healthy tissue, is achieved by using differences in the conductivity of healthy tissue with respect to the affected or target tissue. Target tissue, such as malignant tumor tissue, has higher complex or full conductivity (admittance) than healthy tissue, and thus has a higher absorption rate of the current passing through it compared to healthy or normal tissue, so the formation of Joule heat mainly occurs when current flows through the target tissue.

A prior art hyperthermia device is described in US 2004/0230263 A1. However, it differs from the present invention in the following features: the device of US 2004/0230263 A1 uses dipole antennas (radiation coupling). Radiative RF is applied to the patient or, more precisely, to the target tissue using absorbed RF radiation. In the radiative solution, the target is independent of the circuit; feedback is carried out only by means of the standing wave coefficient (SWR), which shows the reflected power compared to the directed one. The device of the present invention does not use dipole antennas; the proposed device uses a capacitor arrangement, where the patient’s body between at least one electrode and at least one counter electrode is a dielectric material that is part of a conductive circuit. This provides the ability to directly control the target as part of the chain and creates more accurate and clear feedback for process control. In the present invention, capacitor electrodes (capacitor coupling) are used to pass the RF current through the corresponding cross section of the body. This standard device causes phase-shift interference between the antennas and the interference of the standing waves of their radiation in order to adjust the focus to the desired area. In the present invention, the conductivity differences of the respective tissues are used (for example, a malignant tumor tissue has a higher conductivity than healthy tissue), which thus leads to automatic focus selection. This causes immediate consequences for extensible organs such as the lungs or heart, or if the patient moves during a treatment procedure that can exceed one hour. Although the focus in a conventional device remains in the area it was previously focused on, regardless of the actual position of the tumor, the present invention follows any movement of the target, since the RF current automatically flows in the right direction. In this standard device, the target is considered as an electrically independent object that absorbs radiated energy. In the present invention, a target is used as part of an electric circuit, as a dielectric material of a capacitor in a resonant circuit. Thus, the heating process is carried out and controlled in another way. In this conventional device, the UKP (specific absorption coefficient) of the absorbed energy is used as the only heating mechanism to achieve a positive effect. In the present invention, Joule heat (Q = I ² R) is used by converting the flowing current into heat, as well as the potential difference for manifesting an electric field effect. A conventional device controls temperature only as a tool for reproduction and standardization of therapy. In contrast, the present invention uses absorbed energy (J / kg) and patient conductivity (S = 1 / R) to closely monitor treatment conditions. In a conventional device, in implicit form, there is the assumption that the success of therapy depends only on the thermal effect in relation to the temperature reached. Basically, in this way they cause necrosis in the target tissue. However, for the present invention, it is not necessary to achieve such high temperatures at which necrosis occurs, since the action of the field causes apoptosis at lower temperatures. Thus, the proposed device allows you to treat tumors or malignant tissue, malignant tumors, tumors and, in particular, solid tumors, inducing and / or causing apoptosis, whereas conventional devices that use radiation communication, cause necrosis. The device of the present invention does not use radiation coupling and uses a patient and, in particular, a patient’s tissue between the electrodes, where said tissue contains diseased tissue, also called target tissue, as a dielectric material or dielectric as part of an electrical circuit.

Since US 2004/0230263 A1 is considered as the most relevant description of the prior art, the authors of the present invention have summarized the above differences with respect to the present invention. The statement made in relation to the layout of the individual parts of the device for hyperthermia or the technical parameters of the proposed device in comparison with US 2004/0230263 A1, of course, is general in nature and is always true and really not only in relation to US 2004/0230263 A1.

1. US 2004/0230263 A1 is based on RF radiation / absorption processes, and not on RF current conductivity, as the present invention.

2. The multi-antenna solution of US 2004/0230263 A1 focuses energy on the target using a phased array method, which means that their amplitude and phase are individually adjusted to focus correctly. In our case, this happens in a completely different way. In the device of the present invention, focusing occurs automatically by means of differences in the conductivity of the malignant target and surrounding healthy tissues; focusing correction, several antennas, and radiation adjustment are not used.

3. In the case of US 2004/0230263 A1, proper focusing requires a high frequency (130-160 MHz, approximately one order of magnitude higher than the frequency that the proposed device for hyperthermia, which preferably uses a fixed carrier frequency of 13.56 MHz).

4. In US 2004/0230263 A1, the frequency is not a carrier modulation frequency; the modulation described in US 2004/0230263 A1 is used to distinguish between multiple emitting antennas. US 2004/0230263 A1 uses phase modulation (phase shifting devices). In the present invention, one resonant circuit carries an amplitude-modulated signal; in the present proposed device, phase modulation is not used.

5. In US 2004/0230263 A1, the feedback is a fit of the standing wave coefficient, and this provides an optimal connection with the radiated energy. In the present invention, feedback is directed energy, and capacitor coupling is also used.

6. In US 2004/0230263 A1 it is necessary to change the frequency for the best fit in order to achieve the correct adjustment of the phased antenna array. In the present invention, a fixed frequency is set.

7. US 2004/0230263 A1 uses frequencies that are not permitted for free use in hospitals, so a shielded camera is required for legal use. In the proposed device for hyperthermia, a fixed legal frequency allows legal use without costly, dangerous and complex additional shielding. In the frequency range that is used by the device according to US 2004/0230263 A1, do not use such an interval that could be used freely without a shielded camera. In any case, the free frequencies used by the device of the present invention are narrow fixed ranges that do not allow frequency sweep to tune.

8. The frequency used by the proposed device is low and does not exceed 50 MHz. In contrast, the radiative solution must use a high frequency of at least 100 MHz, otherwise precise focusing is not possible. As a rule, an antenna (radiative) needs to be optimized up to 50 Ohms (this is an accepted standard). This function is performed by the tuner. In the present invention, the SWR is important only for the electronic protection of the amplifier (if it deviates significantly from 50 Ohms, it can be destroyed by reflected power). In the present invention, the low frequency, preferably equal to 13.56 MHz, or 6.78 MHz, or 27.12 MHz, or 40.68 MHz, or any value between them, allows the proposed device to contain radiation and enhance only conductivity.

9. The main difference in the design of the devices according to US 2004/0230263 A1 and the present invention lies in the solution with the antenna from US 2004/0230263 A1, which is radically different from the design of the proposed device. To emit, the device according to US 2004/0230263 A1 must contain Hertz dipoles, while the proposed device does not contain and does not need such dipole antennas. To focus US 2004/0230263 A1, a round applicator is needed, the proposed device needs directional current and does not need omnidirectional radiation.

10. The device according to US 2004/0230263 A1 contains a set of antennas that contains several dipoles (several dipole antennas are needed to surround the body), while the proposed device contains a capacitor arrangement (it is a capacitor coupling, not an antenna) containing an electrode and counter electrode.

11. In US 2004/0230263 A1, in order to achieve the best focus, the phase between the antennas (in fact, diffraction coherence, interference) is modulated on the target area, while the present invention uses amplitude modulation and is intended for amplitude modulation.

12. The device according to US 2004/0230263 A1 requires some form of independent focus identification (temperature measurement in an invasive way or by means of MRI imaging, which is quite expensive), otherwise it is not clear where the thermal effect should be focused. The feedback signal in US 2004/0230263 A1 reflects only the sharpness of the focus, and it can be targeted at any area through phase modulation, but you need to know where it is in order to focus the effect. For the present invention, such information is not needed. It is only important to make sure that the RF current passes through the target region, and this can be easily achieved provided that the target region is between the electrodes, i.e. between the electrode and the counter electrode. Of course, when the patient moves, the SWR changes (either with physiological movements, such as breathing or a heartbeat, or with the digestive movements of the stomach or intestines, etc.). In the present invention, the movement (in which the target region remains between the electrode and the counter electrode) does not have any value or negative effect, the current automatically repeats the movement through conduction.

13. Modulation according to US 2004/0230263 A1 is determined by the geometry of the tissue (location and size of the tumor), so this is part of the focus. In the present invention, modulation has no effect on focus; it can be used to activate the mechanism of cell death, enhance apoptosis, instead of necrosis caused by high temperature.

14. In the present invention, the modulation has a pattern that causes a therapeutic effect and which can also be turned off when it is necessary to perform only heating of the target area. Modulation according to US 2004/0230263 A1 must be carried out continuously, otherwise the focus will be lost.

The hyperthermia device of the present invention is particularly useful for the treatment and subsequent treatment of tumors, malignant tumors, metastases and carcinomas, as well as pains and diseases of the central nervous system.

Treatment, follow-up treatment and / or prophylaxis of pain or medical signs of pain include pain caused by a malignant tumor, pain associated with tumors, chronic pain and chronic pain conditions, headaches, migraines, migraine headaches, neuralgia, trigeminal neuralgia, post-therapeutic neuralgia, neuropathic pain, persistent musculoskeletal pain and persistent visceral pain.

Signs of persistent musculoskeletal pain and persistent visceral pain additionally include persistent vertebral pain, persistent neck pain, persistent shoulder pain, persistent joint pain and fibromyalgia.

Pain that can be treated with the proposed device can be caused and / or associated with malignant tumors, tumors, premenstrual syndrome, mastalgia, stomach pain associated with irritable bowel syndrome, and pain associated with carcinoid syndrome.

If the disease lasts for more than 3-6 months, this is referred to as chronic pain. Its causes can be incurable diseases, such as malignant tumors or rheumatic diseases. However, the relationship between pain and the disorder, or, respectively, the disease that initially caused the pain, often can no longer be established, or the original disorder can no longer be treated. In addition, various environmental influences, such as stress or weather changes, can initiate or exacerbate pain. Chronic manifestation of pain often contains various forms of pain.

The most common forms of chronic pain are vertebral pain (among other things, as a result of a herniated disc, a syndrome of compression of the nerve root), headaches (among other things, migraines, tensile type headaches, cluster headaches), rheumatic pains (among others, arthritis, fibromyalgia), neuralgia (among other things, trigeminal neuralgia, pain caused by herpes zoster), pain associated with tumors (inter alia, brain tumor, bone metastases), pain with degenerative disease nyah (among other things, with osteoporosis, arthrosis) and phantom pains (among other things, after amputation, with damage to the nerve plexus).

Often, chronic pain lasts for several years or decades. Often patients with chronic pain have emotional problems. Many patients with pain suffer from inaction and apathy; they experience a sense of hopelessness and despair, complain of anxiety and depression, they feel a sense of restrained self-esteem. Such mental symptoms are alarms of chronicity in general, non-specific complaints of a physical condition, such as problems associated with the intestines (diarrhea or, respectively, stasipation), a sensitive bladder, dizziness, dyspnea, palpitations or chest tightness.

Various mechanisms in the peripheral and central nervous system are involved in the occurrence of chronic pain. The increased sensitivity of painful nerve fibers and their local increased excitability are important pathogenetic mechanisms that are relevant, since peripheral pain perception is involved in the etiology of chronic pain conditions. Other pathogenetic mechanisms include increased pain signals of longer duration and the involvement of usually unused nerve fibers in the spinal cord, which leads to a greater spatial expansion of pain perception. As a result, an increased number of pain potentials coming from the periphery in the brain leads to changes in signal transmission in terms of enhancing pain perception and long-term changes in the processing of pain signals.

Even if stored for only a few minutes, intense pain stimuli can lead to permanent structural and functional changes that enhance the transmission and processing of pain stimuli. These procedures are similar to cellular activity, such as cellular activity, which can be observed in all the more complex processes of neural learning; thus, by analogy, this is indicated by pain memory. In this context, the term pain memory includes the ability of the nervous system to create a trace in memory for the resulting pain stimulation through the entire pain treatment system.

The authors of the present invention received reports from 48 patients experiencing pain, which described how their pain disappeared during treatment with hyperthermia. These patients suffered from pain associated with tumors, rheumatic pain, migraine, joint pain, or other types of pain. Example 5 and FIG. 27 describe changes in pain before and after treatment with hyperthermia, and FIG. 27 clearly shows the positive effects of treatment with hyperthermia. After treatment, approximately 16 patients with acute pain and 8 patients with moderate pain absolutely did not feel any pain, and 5 patients with acute pain began to rapidly relieve pain after treatment, and the remaining patients did not begin to feel noticeable differences in the strength of the pain.

Thus, one third of all patients did not experience pain after treatment, which demonstrated the preferred use of the proposed device for hyperthermia for the treatment of pain of any type.

Oncothermia

Oncothermia is becoming an increasingly recognized method for treating tumors. Using standard oncothermia (without the modulation method and the device of the present invention), the effect of oncothermia in humans has been proven in many retrospective clinical studies. Treatment of metastatic liver tumors is very difficult due to the effective cooling of the powerful blood flow and organ sensitivity due to chemotoxicity from previous treatment. The application of oncothermia to this organ brought pronounced positive results. Colorectal hepatic metastases were the subject of four different studies (Hager ED et al. (1999) Deep hyperthermia with radiofrequencies in patients with liver metastases from colorectal cancer. Anticancer Res. 19 (4C): 3403-3408). The sensitivity of the liver due to chemotherapy in advanced cases (when the failure of other methods of chemotherapy has been proven to be unsuccessful) is easy to observe with combined treatment compared with oncothermic monotherapy. In particular, the device of the present invention can be used to treat metastatic liver tumors and colorectal hepatic metastases.

Pancreatic carcinoma is a fast and aggressive disease, and in this place you can not find too many results of standard hyperthermia. The results of oncothermy presented at ASCO and other conferences significantly improve the achievements of standard methods of treatment. The results were reproduced in six different clinics in two countries, thus, the advantage is confirmed by statistical data. However, the authors of the present invention were again able to show the positive effects of the device of the present invention in the treatment of pancreatic carcinoma, so that another preferred application of the proposed device is the treatment and subsequent treatment of pancreatic carcinoma.

The lungs are also a complex organ for hyperthermia due to constant cooling and ventilation during breathing. Oncothermia due to the nonequilibrium approach is also an excellent treatment for this. Noticeable effects were also achieved by using the proposed device for hyperthermia (see example 6). Thus, the proposed device can also be used with high efficiency for the treatment of lung cancer.

It is described above in detail that the hyperthermia device of the present invention can also be used with high efficiency for the treatment and prevention of various types of pain (see example 5).

It is also possible to treat disorders of the central nervous system (tumors or other disorders of the brain and / or spinal cord). Safe treatment can be clearly demonstrated through documented cases in the area around the eye, when the tumor disappeared by treatment with oncothermia, while after treatment the eyes remained intact, intact (see example 7).

It is also effective to treat pain with both heat and field (TENS = “transdermal electrical nerve stimulation”, TENB = “percutaneous electrical nerve block”) due to a transdermally applied electric field, which is standard practice for this treatment.

The differences between conventional hyperthermia devices and the hyperthermia device of the present invention, as well as between conventional hyperthermia treatment and oncothermia treatment with the hyperthermia device of the present invention are as follows:

1. Conventional RADIATIVE HYPERTHERMIA works only with temperature (the classical idea of Hypocritus). CONDUCTIVE HYPERTHERMIA, which is used in the proposed device, uses the synergistic effect of the electric field and thermal energy (modern biophysical concept). [Note: temperature and heat are definitely different values. Temperature is not a quantitative quantity; it is not proportional to mass or volume. Temperature characterizes only equilibrium. Heat is an active energy that partly raises the temperature, partly modifies chemical bonds and molecular structures, which is the purpose of the present proposed device. For example, a person eats food (absorbs energy from food, measured in kJ) not to increase body temperature. In fact, heat, which is also measured in kJ, does not reflect identical physical parameters.]

2. Conventional RADIATIVE HYPERTHERMIA works by simply absorbing energy; the patient is independent of the electronic device. In a CONDUCTIVE HYPERTHERMIA system, such as the proposed device, the patient is part of an electrical circuit (capacitor), such as a dielectric material. This provides the ability to tightly and strictly control. [Note: it should be remembered that patient monitoring plays a key role, so MRI should be used in RADIATING HYPERTHERMIA treatment, and CONDUCTIVE HYPERTHERMIA does not require this complication.]

3. In ordinary RADIATIVE HYPERTHERMIA use short wavelengths, high frequency [70 MHz - 2400 MHz]. IN CONDUCTIVE HYPERTHERMIA 13.56 MHz is used, which is at least five times lower. [Note: the depth of penetration of electromagnetic waves into the body has a strict inverse dependence on frequency. Penetration of CONDUCTIVE HYPERTHERMIA is approximately 20 cm, and RADIATIVE HYPERTHERMIA (depending on its operating frequency) does not reach one quarter of this value under similar conditions of the patient.]

4. In ordinary RADIATIVE HYPERTHERMIA, artificial focusing is used, which requires very complex software and hardware. CONDUCTIVE HYPERTHERMIA has a self-selection mechanism (self-focusing) by selecting RF conductivity. [Note: the tissue of the malignant tumor has an increased conductivity compared to healthy tissue, so the RF current used in CONDUCTIVE HYPERTHERMIA automatically selects this direction.]

5. RADIATIVE HYPERTHERMIA does not use focus correction due to patient movements (for example, breathing), so there is a danger of incorrect focusing or more focus than necessary. CONDUCTIVE HYPERTHERMIA automatically corrects this through the above self-selection.

6. Conventional RADIATIVE HYPERTHERMIA requires sophisticated patient preparation and very sophisticated management. CONDUCTIVE HYPERTHERMIA is a simple, easy-to-use, and cost-effective way.

Description of the invention

The present invention relates to a radio-frequency device for hyperthermia for establishing a capacitor coupling with conductive electrodes, passing an RF current between them, without a dipole antenna that contains a radio frequency source (1), an amplifier (2), a sensor (3), optionally a feedback amplifier ( 6) and a modulating signal generator (13), where the radio frequency source generates a source signal (8), which is modulated by a modulating signal generator (13) to generate a modulated source signal (10), modulated the source signal (10) is amplified by an amplifier (2) and sent to the target (17), and the sensor receives a feedback signal (5) from the target, which is sent to the feedback amplifier (6), if present, where the feedback signal (5) amplified by a feedback amplifier (6), if amplification is necessary, and the feedback signal (5) modulates the source signal (8) to generate a modulated target signal (4). Thus, important parts of the device are the radio frequency source (1), amplifier (2), sensor (3) and the modulating signal generator (13). In addition, the presence of a feedback amplifier (6) is also preferred, but this is not necessary. All additional parts are not necessary and are not required, but are needed for certain preferred embodiments.

The proposed device is described with reference to figures 1-7. In the figures, parts of the proposed device are numbered as follows.

(1): a signal generator (oscillator - radio frequency source) that provides a selected frequency (preferably 13.56 MHz) through a fixed undamped quartz oscillator,

(2): an amplifier (RF) that provides the necessary energy for conductive heating, where the tuning device optimizes the conductivity for an individual patient,

(3): a unit for sampling the feedback sensor signal (current / power) (RF current sensor), which controls the directional power of the source and the reflected power of the target,

(4): x (t) is the signal amplified and modified by the target (modulated signal), which is responsible for the effect in the target tissue,

(5): a feedback signal that carries information about the actual impact in a complex form and provides control over it,

(6): a feedback amplifier that amplifies the feedback signal to the desired level for future use,

(7): in FIGS. 6 and 7: amplified feedback signal corresponding to (5) in FIGS. 1-5,

(8): F (t) is a carrier signal, which is an RF power signal (preferably with a frequency of 13.56 MHz) corresponding to an amplitude-modulated signal by a modulator (9),

(9): a modulator that performs amplitude changes,

(10): a modulated signal, which may look as shown in FIG. 13,

(11): a multiplier (feedback correction for modulation) that adjusts the modulation to the corresponding feedback,

(12): a modulating signal that represents “information” carried by a carrier wave (preferably at a frequency of 13.56 MHz),

(13): a modulating signal generator (e.g., a pink noise generator) provides a modulating signal; 5, a modulating signal generator (13) (for example, a pink noise generator) is presented as one important part of the proposed device,

(14): optionally, a signal verification unit (power / current sensor) that measures the amplitude of the signal for monitoring purposes,

(15) optionally comparing device with a standard signal (P _a (t)), which controls the signal by comparison with the standard,

(16): optionally, a standard signal (P _a (t)) as a stable signal for the latch signal levels,

(17): load (target tissue to be exposed), mainly the patient, and

(18): RF ground, an initial level that is not necessarily identical to the overall ground level (ground potential). This earth is modified by an appropriate distribution of the potential of the RF signal as a function of its wavelength.

In the conventional art system, as shown in FIGS. 1 and 2, a sensor (3) is used only to measure the strength of a signal (8) directed at a target from a signal source (1), but without the use of modulating feedback and / or amplitude modulation . Modulation can be applied to the output signal of the sensor (3), but in this case the modulation point goes after the gain point, and modulation feedback cannot be applied.

Figure 5 provides a simplified view of the proposed device. The following description of the operation of the proposed device is based on the structural diagram of the operation of the device provided in FIGS. 6 and 7. FIGS. 6 and 7 show both the main (power) circuit necessary for any treatment of hyperthermia, including standard treatment of hyperthermia, and an additional circuit ( i) the modulation required for the proposed device.

The present invention relates to a radio frequency (RF) device for hyperthermia, which contains a radio frequency source (1), an amplifier (2), a sensor (3), a feedback amplifier (6) and a modulating signal generator (13), but does not contain one or more dipole antennas, where the radio frequency source (1) generates a source signal (8), which is modulated by a modulating signal generator (13) to generate a modulated source signal (10), the modulated source signal (10) is amplified by an amplifier (2) and sent to a mish (17), from the target (17) the sensor (3) receives the feedback signal (5), which is sent to the feedback amplifier (6), where the feedback signal (5) is amplified by the feedback amplifier (6) and modulated by it source signal (8) for generating a target-modified modulated source signal (4). This radiofrequency (RF) device for hyperthermia is intended to increase the selectivity of hyperthermia treatment. Also in this embodiment, the presence of a feedback amplifier (6) is preferable, but not necessary, if the feedback signal has sufficient power and does not require amplification.

In the event that the feedback amplifier (6) is not necessary, or in the case when the feedback amplifier (6) is integrated into the modulating signal generator (13), the proposed hyperthermia RF device using a capacitor coupling contains a radio frequency source (1 ), an amplifier (2), a sensor (3) and a modulating signal generator (13), possibly with an integrated amplifier function, but does not contain one or more dipole antennas, where the radio frequency source (1) generates a source signal (8), which is modulated by generator and a modulating signal (13) for generating a modulated source signal (10), the modulated source signal (10) is amplified by an amplifier (2) and sent to the target (17), the sensor (3) receives the feedback signal (5) from the target (17) ), where the feedback signal (5) is optionally amplified by a modulating signal generator (13), and it modulates the source signal (8) to generate a target modulated source signal (4).

The modulated source signal (10), as well as the modulated source signal (4) modified by the target, is supplied to the target by capacitor coupling, and not by radiation or radiation coupling. Capacitor coupling is carried out between at least two conductive electrodes, i.e. at least between one electrode and at least one counter electrode, causing an RF current between them. This means that RF current flows between at least two conductive electrodes. Thus, the device of the present invention uses conductivity between a pair of opposite electrodes and does not use radiation between the electrodes forming the antenna.

The RF current flowing between the electrodes has the advantage that it independently finds the target region and does not require any focusing. In addition, the electric field generated between the conductive electrodes induces apoptosis and kills, for example, malignant cells through apoptosis rather than necrosis, as is the case with radiation coupling, which also kills healthy cells and mainly kills healthy cells when the radiative effect is not focused well.

It is very important to emphasize that in the radiative solution there is a global choice of the area of influence or the cells that are affected, i.e. all cells within the macroscopic region die when this region is heated, regardless of whether the cells are malignant or not. In these conventional devices, focusing is attempted by phase modulation (phased array) of heating in the region where the solid tumor is located so that the tumor cells preferably die.

In contrast, in the case of the device of the present invention, the selection occurs automatically at the cellular level due to the use of cellular differences between healthy and tumor or malignant cells. The metabolic rate between healthy or normal cells and tumor or malignant cells is differentiated by their ionic environment and, therefore, by their impedance. Therefore, it is also very important that, due to this fact, the device of the present invention can also be used to treat metastases of malignant tumors, and not just solid tumors, since it is necessary to focus the heat generated by devices of the prior art in a macroscopic or larger area, and the proposed device can also kill individual malignant cells and metastases of malignant tumors due to cell differences at the microscopic level.

Thus, due to the use of the electric field (approximation of the near field) by the proposed RF device for hyperthermia, where the electric field has an effect at the cellular level (membrane deformation), this device is superior to conventional devices that use the radiative solution using the Poynting vector ( vector product or magnetic and electric fields) that can only be used to generate heat.

In addition, in the present proposed device using amplitude modulation, rather than phase, as in conventional devices of the prior art.

The term “target,” as used herein, refers to an object (ie, a patient, person, or animal) to be treated with hyperthermia or oncothermia.

The term “target region” refers to a part of the body of the target that is located between the electrodes and which contains a malignant, affected, or painful region or tissue or cells.

The term “target tissue” refers to malignant, diseased or diseased tissue or cells.

Modulation is aimed at adjacent contacts (“social signals”) of the cell. Malignant cells act autonomously, since their contacts are broken due to their temporal-fractal fluctuation. In contrast, healthy cells have such compounds, they act together and undergo strict regulation in a temporally fractal manner. The proposed modulation of the signal is very complex. After receiving the signal, demodulation is required (information extraction, media separation). The simplest method is to use a pair of amplitude modulation-demodulation, since the modulation is only a change in the "strength" of the signal through the information that needs to be transferred, and demodulation is a simple cleaning by cutting off the symmetric signal (see Fig. 14).

When a non-linear signal is received from the receiver, asymmetry is needed for demodulating cleaning. The approach of one solution to the demodulation problem is stochastic resonance. This application has shown that an amplitude modulated signal can exhibit stochastic resonance.

In conclusion, each small amplitude modulation of the carrier frequencies (if the modulation is selected from the stochastic resonance frequency) can cause a certain resonant effect in each Markov case with two states (for example, an enzymatic process, voltage-dependent ion channels, etc.). Due to the very large number of such possible reactions in a living organism, these microscopic effects lead to macroscopic results.

The use of a sensitivity threshold can serve as a simple explanation of an effect similar to demodulation mediated by stochastic processes. White noise (uncorrelated, normal distribution around the zero level) does not show any regular pattern (pattern) (see Fig. 15). Adding (modulating) a deterministic signal with a low or high frequency, but with a low amplitude, apparently does not change the nature of the noise (see Fig. 16). However, if there is a sensitivity threshold that cuts off the main part of the wave amplitude and reflects only high above-threshold amplitudes, then amplitude modulation (or simple summation) becomes available for observation, and the deterministic signal can be restored above the threshold level (see Fig. 17). Threshold clipping is not a true modulation, but it leads to a similar effect. There is a minimum starting at which the above-threshold signal becomes recognizable, and another level at which the threshold is so low that almost all noise can go unfiltered, and a maximum between these two levels. The threshold with a fixed noise amplitude can be changed, but it seems that in practice in living objects this threshold is fixed. In this case, the amplitude can be increased until a threshold is reached at an appropriate level. Of course, in this way, a mixture of deterministic waves can be recognized (see FIG. 17A and FIG. 17B).

It can be shown that there is an ac field effect on enzyme activity and signal transmission. In clinical studies, it has been shown that an AC electric field can inhibit the spread of metastases of a solid lung tumor. It is also possible to directly apply a low frequency current without the need for any demodulation. The success of the use of alternating current does not affect the modulation-demodulation approach, since the use of the carrier frequency serves to target the selected structure (deep tissue, membrane effects, etc.). There are various points of view on modulation-demodulation.

The hyperthermia RF device of the present invention uses a capacitor coupling, an inductive coupling or radiation coupling, and preferably a capacitor coupling and alternating current and radio frequency (RF) waves.

In more detail, the present invention relates to a radio-frequency device for hyperthermia, which modulates the radio frequency (RF) signal of the source (8) directed to the localized target region (17), and, therefore, increases the selectivity of hyperthermia treatment of the localized target region. Preferably, the RF signal (8) has a free industrial frequency, such as 13.56 MHz, or a doubled or tripled frequency of 13.56 MHz. The first modulation of the signal (8) is performed by a modulator (9), which receives the modulating signal (12) from the modulating signal generator (13) and the source signal (8) from the signal generator (1) and converts these signals into a modulated signal (10), which is then amplified by an amplifier (2) and delivered as an amplified and modified signal to the target region (17). Preferably, the modulation is amplitude modulation to cause demodulation by stochastic resonance, as described above. Modulation can also be done by pulses, when the length and time division of the signal are modulated by a predetermined noise (preferably “colored” noise). The amplified and modulated signal, together with the reflected signal from the target area (17), is sent by the sensor (3) as feedback from the first signal directed to the target area. This feedback signal (5) is sent to the feedback amplifier (6) if the feedback signal does not have sufficient power and requires amplification. Then, the amplified feedback signal (7) can, preferably by means of an additional modulated signal (12), modify the source signal (8) emitted by the signal source (1) to generate the target-modified signal (4). Also, the amplified feedback signal (7) can provide feedback adjustment for the modulating signal provided by the modulating signal generator (13) on the multiplier (11) to provide an additional modulated signal (12) to the modulator (9) for generating the target modified signal (4 )

The modulating signal source (13) is preferably a pink noise frequency generator (1 / f noise). Pink noise has fractal fluctuations (time interval) and is widely effective for influencing dynamic processes in a given target tissue / cell. Preferably, this is used for amplitude modulation.

A modulating signal (12) modulates the source signal (8) to create a modulated signal (10) by amplitude modulation, frequency modulation, or phase modulation. Preferably, the signal is modulated by amplitude modulation, as described above.

In the proposed device of the present invention, the sensor (3) is used to determine the feedback signal (5) from the target area (17) and this information is used to adjust the amplitude for the optimized modulation / demodulation process, frequency spectrum (preferably pink noise) of the modulating signal (12 ) and modulate the carrier frequency (8) emitted by the signal source (1) through the feedback loop. The sensor (3) determines the standing wave coefficient (SWR). This coefficient measures the correct correspondence of RF energy, which is the coefficient between the sum and the voltage difference of the transmitted and reflected signals

The feedback sensor (3) can be placed in front of the target tissue (17), as shown in Fig.6, or after the target tissue (17), as shown in Fig.7. For example, as shown in Fig.6, the sensor (3) is located between the amplifier (2) and the target (17), or, as shown in Fig.7, the sensor (3) is located between the target (17) and the feedback amplifier (6 ) However, signal modulation must occur in front of the target tissue (17).

Signal check block (power / current sensor) (14), comparing the device with the standard signals (P _a (t)) (15) and the standard signal is (P _a (t)) (16) are optional additions to the proposed device, which can be used to fine-tune feedback and modulation.

Chelomei's pendulum theory

The present invention uses the Chelomei pendulum theory to modulate the source signal (10). This theory can be described as follows:

Starting point in a nonlinear differential equation

where L is a linear integro-differential operator.

For functions F and f, the following conditions apply:

- in time F changes slowly relative to f,

- F and f can be normalized, and the norm for f is less than the norm for F,

- f is a quasiperiodic function t,

- the average value of f with respect to t is zero.

The average value is obtained by the upper limit. So the solution of equation (1) in

obtained by satisfying the condition

Then, assuming that the value of ξ is less (namely, expansion in a series can be completed on the second term), equation (1) can be written in the form

Averaging the equation over the period of a rapidly changing exciting term, the average value is obtained by solving the equation

It is believed herein that F changes slowly over time. Therefore, her average is equal to herself.

, следует, что только члены

уравнения могут давать -ξ. Таким образом, из (4) следует уравнениеThis equation can be solved if the time function ξ (t) is known. From the assumption that

, it follows that only members

equations can give -ξ. Thus, from (4) follows the equation

This is a linear differential equation with respect to ξ. If we assume that in this equation X is a constant that changes slowly with time, then X will thus be a solution parameter. If f is sinusoidal, this gives

Since a stable solution is of interest, complex functions of time are considered in equation (6).

The solution to the equation is

Substituting this into equation (5), the averaged solution is the differential equation

,

,

from which we can conclude that a term rapidly changing in time can change the solution of the equation. If it does not have the character of a sinusoid, but is periodic, then equation (8) must be solved for each component. In this case (10) is as follows:

The method can be similarly used for stochastic processes using the Fourier transform. The above relation can be converted into an equivalent form in order to generalize it to arbitrary signals

From this, arbitrary signals give:

то получаютIn particular, if the high-frequency excitation is pink noise, namely if

they get

where Ω * is greater than the angular frequency of another exciting term.

Application of this method to hyperthermia

In accordance with the above conclusion, the method can be applied if the rapidly changing exciting term depends on the solution of the equation. To apply this to hyperthermia, the following terms are needed: one first harmonic excitation, which should not depend on the solution of the equation (a strictly defined source), and one or more high-frequency harmonics. However, the superposition of two sources should be subordinated, for example, to capacitive control. Thus, the applicability of the Kapitsa method is shown, f depends on a slowly changing solution of the equation. The following figure shows such a case, amplitude modulation of high-frequency harmonic. Thus, a rapidly changing exciting term depends on the decision.

Detailed case analysis

The case considered can be applied to the polarization of the bias. If this is a first order effect, then

and if the differential operator is chosen for the damped oscillation:

A strictly defined source should not depend on X, therefore,

Then the equation is as follows:

The solution to the equation for the steady-state amplitude is:

Whereas for the phase shift:

If X represents the polarization and F ₀ represents the electric field, then the dielectric susceptibility is

Since Ω is the angular frequency of the first harmonic excitation, focus on Ω. Thus, the susceptibility and permittivity can be influenced, since the second term in the denominator controls the resonant frequency. The susceptibility can be significantly modified around the resonance ω≈ω ₀ , which is also valid for its sign.

Additional generalization

Using this, one can consider orientational polarization. Starting with a nonlinear differential equation,

where L and G are linear integro-differential operators. The functions F and f should be subject to the above limitations. It is assumed that for the operator G there is an inverse operator and it is denoted as G ^-1 . Instead of (23), we can consider the following equation:

Then the decision will take the form

thus satisfying the condition

The equation

denotes the rapidly changing part where it is assumed that dF / dx≈0.

When returning to the original equation

excitation

will be harmonious. Consequently, we can move on to the complex functions of time.

where it should be taken into account that X changes in time slowly at f ₀ (X). A solution must be found in the form

Then the complex amplitude will look like this:

Next, the averaged time function is obtained by solving the equation:

The results can be generalized to an arbitrary function of time. First, the above relation is rearranged into an equivalent form and generalized to the case of a linear spectrum.

For this arbitrary signal receive:

, то получаютIn particular, if the high-frequency excitation occurs through pink noise, namely

then get

where Ω * is greater than the angular frequency of another exciting term. If X is linear in f ₀ (X) in equation (30), then the above equation takes the form

If the angular frequency ω is of great importance, then a high-frequency approximation can be used. If the excitation is harmonious with a complex function of time

then the complex amplitude will look like this:

The question of how to get the Kapitsa equation considered above still remains open. A method for this is shown in FIG. As can be seen in FIG. 23, in practice one can speak of positive feedback, where the feedback signal is subjected to high-frequency full modulation.

Orientation Debye Polarization

If the effect is first order, namely

and if the differential operator of the damped oscillation is selected as follows:

if there is no high-frequency excitation, then

And relative permeability is equal

which corresponds to the Debye polarization. In the case of low frequencies, we can see that

whereas for high frequencies apply

In the case of Debye polarization, the condition

If high-frequency excitation takes place, then the complex amplitude will be

Then the permeability is equal

In the case of low frequencies, we can see that

in the case of high frequencies, the permeability is taken equal

In theory, it is possible that this high-frequency permeability has a negative value. As a result, force lines will be pushed out. This principle can be used for levitation. Namely, by choosing the sign and amplitude for K, it is possible to influence the permeability. When considering the high-frequency approximation, get

In this document, the mark is independent of the mark of the derivative.

Rapidly changing excitation depending on speed

Consider a nonlinear differential equation

where L and G are linear integro-differential operators. The restrictions described above remain applicable to the functions F and f. It is assumed that for the operator G the inverse operator exists and is denoted by G ^-1 . Instead of (23), we can study the following equation:

Solving an equation in the form

will be found when the condition is satisfied

The rapidly changing part denotes the equation

where it is assumed that dF / dx≈0. Now, back to the original equation

excitation

will be harmonious. Consequently, we can move on to the complex functions of time.

. Решение будет найдено для формыwhere it should be taken into account that dX / dt changes slowly with time in

. A solution will be found for the form

Then the complex amplitude will have the following form:

The complex amplitude of the velocity is

Now the averaged function of time follows from the solution of the equation

If dX / dt is linear in f ₀ (dX / dt), then the above equation takes the form

If the angular frequency ω is high, then a high-frequency approximation can be used. If the excitation is harmonic with a complex function of time

then the complex amplitude will have the following form:

The permeability for the Debye case will have the form

In the case of low frequencies you can see:

In the case of high frequencies, you can see:

Therefore, by applying this control, high-frequency capacitive bypass can be eliminated.

Rapidly changing excitation depends on acceleration

This can happen, for example, if the mass oscillates at a high frequency. Classically, this method can be used if the oscillatory effect of vacuum is considered. The starting point will be the differential equation:

The restrictions described above remain applicable to the functions F and f. It is assumed that for the operator G the inverse operator exists and is denoted by G ^-1 . Instead of (20), the following equation is investigated:

A solution to this equation will be found in form (2) by precisely defining requirement (3). Then the decision will take the form

thus satisfying the condition

For a rapidly changing part, the equation has the form

where it is assumed that dF / dx≈0. Now, back to the original equation

excitation

should be harmonious. Therefore, we can pass to the complex functions of time in the form

меняется медленно со временем в

. Решение должно быть найдено в формеwhere it is taken into account that

changes slowly over time in

. A solution must be found in the form

Then the complex amplitude will have the following form:

The complex amplitude of the velocity has the form

Now the averaged function of time follows from the solution of the equation

является линейным в

, то приведенное выше уравнение принимает формуIf

is linear in

, then the above equation takes the form

If the angular frequency ω is high, then a high-frequency approximation can be used. If the excitation is harmonic with a complex function of time

then the complex amplitude will have the following form:

Then the permeability for the Debye case will be

In the case of low frequencies you can see:

and in the case of high frequencies:

Thus, using this control in the case of not very high frequencies, capacitive bypass can also be eliminated. High frequency control can also be combined. For example, excitation may depend on displacement and speed. In mechanics, a similar result is obtained by accelerating the coordinate system by performing fast angular oscillations of low amplitude, in which centrifugal force and Coriolis force are applied.

Generalization of the Kapitsa method for vector processes

The use of hyperthermia in a person to be treated can be modeled by a layered dielectric material, where each layer is a parallel rheostat-capacitor coupling. Therefore, each layer is divariant. Thus, it is important to generalize the theory of vector processes. The following equation should be studied:

If the matrix operator is invertible, then the above equation can also be expressed in the form

If the solution function is decomposed into the middle (created by the carrier frequency signal) and rapidly changing part (created by the high-frequency signal):

where the Kapitza assumptions described earlier should be made. The following two equations for the two parts of the decomposition result:

If the high frequency signal is sinusoidal:

then the solution of the above equation is also sinusoidal, and the complex amplitude can be calculated from the matrix equation

Substituting this into the first equation (4), we obtain an average solution for the carrier frequency:

If the second term on the right side of the equation is a linear function of the averaged solution, namely

then the previous equation will be linear:

If F is sinusoidal, i.e.

therefore, solution (9) is

If the dependence is not in accordance with (95), but depends on speed or acceleration, then the solution will take the form

The equations can be generalized, as shown earlier, for several functions of high-frequency excitation.

Detailed permeability analysis using the Kapitsa method: lossy capacitor

If the field strength of the capacitor is E, then a current density will occur

In the case of harmonic nutrition, the equation can be expressed in the following form:

The power dissipated per unit volume is

where the asterisk denotes pairing.

Debye Capacitor

Take an ideal capacitor and a lossy capacitor connected in series (see FIG. 24). The total permeability of the circuit is

It can be rearranged as follows:

It is easy to show that the above form is identical to the form given earlier:

To accurately determine the Debye loss, complex permeability should be determined. From equation (105) it follows

In this way

High frequency lossy capacitor control

For the field strength of the capacitor, a signal will be used that is proportional to the current density of the capacitor, but shifted in phase. A schematic diagram of this solution can be seen in Fig.25.

In accordance with the foregoing, for the circuit in the figure, a differential equation is obtained

From this, as described previously, receive

If the power is harmonic and if the second term is a homogeneous function of the current density, the Kapitsa equation is obtained

whose relative permeability is

Cases

1. Control is proportional to current density. In this case, K (ω) is a real number less than unity, so we get

1.a. If τΩKσ >> 1, Kσ <1, then

Thus, the material part decreases, while the imaginary part increases and changes its sign.

1.b. If τΩKσ << 1, Kσ << 1, then

Thus, the material part and the part with losses will increase.

2. Inverse phased control proportional to current density. In this case, K (ω) is a real number less than one. From equation (11) get

2.a. If τΩKσ >> 1, Kσ <1, then

Thus, the material part decreases, while the imaginary part increases.

2.b. If τΩKσ << 1, Kσ <1, then

Thus, the material part (to a large extent) and the part with losses will increase.

3. Control proportional to current density, with a phase advance angle of 90 °.

In this case, K (ω) = iK. The relative complex permeability will be

3.a. If Kσ << 1, then

In this case, both permeabilities are reduced.

3.b. If KστΩ >> 1, then

Thus, both permeabilities are reduced.

4. Control proportional to current density with a phase delay angle of 90 °.

In this case, K (ω) = - iK.

4.a. If Kσ << 1, then

Consequently, both permeabilities increase.

4.b. If KστΩ >> 1, then

Thus, both permeabilities change sign and decrease.

High Frequency Debye Capacitor Control

The control is performed in accordance with the above figure, the only difference is the use of a Debye capacitor. The dependence between the current density and the field strength of the capacitor has the following form:

If we introduce the differential operator d / dt instead of iω, we obtain the equation of motion

where the presence of high-frequency excitation is taken into account. For the sake of simplicity, the following operators are introduced:

In the case of harmonic excitation for a rapidly changing part, it follows from this that the complex amplitude of the current density is

For a part with a carrier frequency:

If the field density is harmonic and the second term on the right side of the equation is a homogeneous linear function of the current density, then the algebraic equation

from which complex relative permeability:

After performing the transformations receive

where ε _e represents the initial relative permeability.

Cases

1. Control proportional to current density. In this case, K (ω) is a real number less than one. In this way

where τ _ν = ε ₀ ε _e K. If τ _ν = τ, then

From this it can be seen that the low-frequency permeability remains unchanged, the high-frequency permeability converges to zero, the imaginary part has a negative value and

2. Inverse phased control proportional to current density. In this case, K (ω) is a negative real number less than one. In this way

where τ _ν = ε ₀ ε _e K. If τ _ν = τ ₁ , then

From this it can be seen that the low-frequency permeability remains unchanged, the high-frequency permeability converges to zero and the imaginary part is

3. Control proportional to current density, with a phase advance angle of 90 °.

Then K (ω) = iK and, therefore,

This follows from the fact that the Debye capacitor does not change at a low frequency, but at a high frequency:

Thus, the permeability of the material and imaginary parts is reduced.

4. Control proportional to current density with a phase delay angle of 90 °. In this case, K (ω) = - iK, thus

This follows from the fact that the Debye capacitor does not change at a low frequency, but at a high frequency:

Thus, the permeability of the material and imaginary parts decreases and changes its sign. The possibility of technical implementation of the investigated control cases has not yet been described. In principle, the implementation is simple. The slowly changing capacitor current is determined. The current is phase shifted by a phase shifter. The signal generated in this way is transformed into potential by means of a current-voltage converter and multiplied by a rapidly changing sinusoidal signal. This signal is summed with the low frequency signal.

The modulated signal improves the treatment, since the physiology of the fractal creates special characteristics of noise in the form of a “social signal” in biological objects. Malignant cells have autonomy (called Weinberg renegades) and are in constant competition with other cells for nutrients and living conditions. Healthy cells, as a rule, behave collectively, their control is carried out through "social signals", there is no actual competition, only division is active. This means that active ion exchange near malignant cells (in most cases) occurs more intensively than in their healthy counterparts. These signals differ in malignant and healthy tissues. Signal absorption and signal feedback are dependent on tissue properties that optimize selective absorption. The most important parameter for effective action on the target tissue is the SWR measurement, which accurately determines the extent to which the target absorbs the operating frequency.

Modulation of the pink noise generator increases the effect of the modulated signal on the target tissue, since most physiological effects have an exchange of pink noise signals, while malignant tissue does not, so modulation of pink noise selectively damages the malignant tissue. Living systems are open dynamic structures that carry out processes of random stationary stochastic self-organization. The self-organization procedure is determined by the spatio-temporal-fractal structure, which is similar to itself both in space and in time. Special noise (called pink noise, temporary fractal noise) - as a characteristic feature of self-organization - is a typical and general behavior of living biological material, with the exception of randomly organized tumor cells. A biological system based on cyclic symmetry and having an infinite number of degrees of freedom is arranged through the principles of self-organization. On this basis, a new approach to a living state has been developed: fractal physiology. In living systems, stochastic processes exist instead of deterministic actions, so predictions always contain random, unpredictable elements.

This power spectrum is characterized by the so-called pink (1 / f or flicker) noise. Basically, a stationary self-similar stochastic process repeats pink noise if its power spectral density function is proportional to 1 / f. Owing to self-similarity and stationary stochastic processes of biological systems, all of them are pink noise generators a priori. However, a randomly structured tumor does not have this property. A linear system excited by white noise with an infinite number of degrees of freedom and cyclic symmetry emits pink noise. It works like a special filter that creates 1 / f noise from the spectrum of uncorrelated white noise measured before. The tumor system does not have such filtering. Therefore, for the treatment of malignant tumors, modulation of the pink noise generator is important, but for other diseases (for example, when the cells are not organized randomly), a different spectrum may be useful.

Thus, the proposed device can also operate without a feedback amplifier (6) or without a modulating signal generator (13), such as a pink noise generator, as shown in FIGS. 3 and 4. This will lead to modulation of the mixed spectrum, which can be used for applications other than the treatment of tumors, such as the treatment of pain, disorders of the central nervous system and other disorders where the exchange of biological information between cells and parts of the body occurs incorrectly. Pain relief through heat has already been noticed by ancient doctors and can also be achieved through the use of hyperthermia and through an electric field (the effect of percutaneous electrical stimulation of nerves). All patients with tumors experienced pain relief during treatment with oncothermia using the proposed device and reported a relaxed, convenient exposure time, in most cases they fell asleep during the exposure process lasting one hour.

In contrast, conventional devices did not use modulation. The goal of conventional hyperthermia is to achieve the highest possible temperature, and the carrier frequency of the source is sufficient for this.

Modulating the frequency of the source signal (8) by means of the feedback signal (5) has advantages: additional information obtained from the feedback provides an increase in information compared to a simple indiscriminate effect of power. This information makes it possible to select and optimize the distribution of actual energy, and more efficient delivery of actual energy to the target tissue. Thus, the proposed device for hyperthermia is able to selectively heat the target tissue, which may be a tumor, cancer, malignant, inflamed tissue or tissue that is otherwise different from normal or healthy tissue. The proposed device does not perform indiscriminate heating of the body region containing the target tissue, as well as normal or healthy tissue without differentiation. Thus, the modulation used in the present invention increases the specificity for the target tissue and, thus, the selective generation of heat within the target tissue, while avoiding or significantly reducing the heating or excessive heating of the surrounding normal or healthy tissue.

In the case of treating tumor tissue with hyperthermia using conventional devices, one power indiscriminately heats both healthy tissue and tumor tissue and heats all tissues in accordance with the law of absorption of electromagnetic waves of a given frequency, power and, of course, the target substance. Thus, in classical hyperthermia, all tissue is heated, and success depends on differences in the sensitivity of healthy tissue and tumor tissue to heat, while heating healthy tissue around the tumor tissue promotes tumor growth and proliferation of malignant cells due to increased delivery of nutrients to the affected tissue due to increased blood flow. Thus, it is undesirable to heat healthy tissue in the vicinity of the desired and, in particular, tumor or malignant tissue.

Temperature is an intense equilibrium parameter. Physiological mechanisms, mainly blood flow and lymph flow, quickly make it homeostatic (stationary equilibrium), regardless of its effect on healthy and malignant cells. This means that the effect of hyperthermia, achieved with conventional hyperthermia devices, is selective only because of the independent choice of cells: healthy collective cells withstand more stress than individual malignant cells due to their collective interactive mechanisms and mechanisms that reduce stress. Chaperone proteins play an important role in chemothermotherapy. Chaperones (stress proteins or heat shock proteins (HSP)) are very conservative proteins that are vital for almost all living cells and are located on their surfaces throughout their life span, regardless of the evolutionary stage. With any type of change (external stress, various pathogenic processes, diseases, etc.), the dynamic balance of the cell activates their synthesis. Chaperone secretion is the cell’s response to stress in order to adapt to new challenges. As a result of stress, chaperones appear on all malignant cells to adapt to current stress, which thus helps the tumor cells survive. In addition, heat shock proteins are induced by all cancer treatments aimed at eliminating a malignant tumor, such as conventional hyperthermia, chemotherapy, and radiation therapy.

It has been shown that even phototherapy induces the synthesis of HSP. When adapted to stress, induction or overexpression of HSP mainly provides effective protection for cells against apoptosis, but when they are located on the extracellular side of the cell membrane, they have the opposite effect: they present a signal to the immune system that a defect occurs in the corresponding cell. In addition, the induction of various HSPs (HSP27, HSP70, HSP90) was observed in a variety of metastases, and the HSP90 homolog GRP94 protein can function as a mediator of metastasis. In general, HSPs weaken the effect of hyperthermia treatment by increasing tumor cell survival. Strong induction can cause some type of thermal stability of the tumor and, at the same time, resistance to drugs and radiation. Heat treatment can also lead to multiple drug resistance.

The lower resistance of the tumor tissue to stress is the selective idea of most conventional systemically administered chemotherapeutic treatments. The choice is not related to the chemical properties of the drug, but instead relies mainly on the chemical properties of healthy cells and the cellular structure of the malignant tissue.

Thus, the present invention shows an important difference: the input energy carries information and is selective, at least in synergy with selective factors of the target cell structures. Therefore, when using the proposed device, focusing energy on the target tissue is not as important as in classical hyperthermia, since the proposed device provides an independent choice, i.e. some form of auto focus.

Thus, the present invention is also directed to a modulating feedback circuit that includes a feedback amplifier (6) for amplifying a feedback signal (5), preferably, but not necessarily, a multiplier (11) for providing an additional modulated signal (12) to a modulator ( 9), a sensor (3) for detecting a reflected or transmitted signal from a target area (17), a modulating signal generator (13), which is preferably a pink noise generator, for modulating or additional modulating the signal and feedback (5) and a modulator (9) for receiving a modulating signal (12) from a modulating signal generator (13). A modulating signal (12) is generated by a modulating signal generator (13) from a feedback signal (5) by modulating a feedback signal (5).

In this regard, the present invention also relates to the use of a modulating feedback circuit, which comprises a feedback amplifier (6) for amplifying a feedback signal (5), a sensor (3) for detecting a reflected or transmitted signal from a target (17), a modulating generator signal (13) for modulating or additional modulating the feedback signal (5) and for generating a modulating signal (12) for creating a radio-frequency device for hyperthermia according to any one of claims 1 to 8, which can be used for prevention, treatment and the following treatment of tumors, malignant tumors, metastases, carcinomas, pain, migraines and central nervous system disorders. The modulating feedback circuit may further comprise a modulator (9) for receiving a modulating signal (12) from the modulating signal generator (13).

Moreover, if the feedback signal (5) has sufficient power and does not require amplification, then the feedback amplifier (6) is not necessary, and thus, the present invention relates to the use of a modulating feedback circuit that contains a sensor (3) for determining the reflected or transmitted signal from the target (17), a modulating signal generator (13) for modulating or additionally modulating the feedback signal (5) and for generating a modulating signal (12) for creating a radio frequency device for hypertherms and according to any one of claims 1 to 8, which can be used for the prevention, treatment and subsequent treatment of tumors, malignant tumors, metastases, carcinomas, pain, migraines and central nervous system disorders. The modulating feedback circuit may further comprise a modulator (9) for receiving a modulating signal (12) from the modulating signal generator (13).

This modulating feedback chain is used to create the proposed RF device for hyperthermia, which can be used for the treatment and subsequent treatment of tumors, pain in malignant tumors, migraine and central nervous system disorders, as well as for the prevention of pain, migraine, the formation of malignant tumors, education tumors and the development of disorders of the central nervous system.

In addition, the present invention relates to an RF device for hyperthermia, which contains a modulating signal generator (13), which preferably is a pink noise generator for modulating the signal (4), which is supplied to the target area (17), where the signal (4) modulate in such a way that increases the selectivity for the target tissue so as to selectively raise the temperature or heat the target tissue, but not surrounding healthy tissue, up to 42 ° C, preferably up to 45 ° C.

Thus, the present invention also relates to the use of a modulating signal generator (13) for creating an RF device for hyperthermia for the treatment and subsequent treatment of tumors, pain in malignant tumors and disorders of the central nervous system.

In addition, the present invention relates to a method for treating diseased tissue, in particular tumor, cancer, malignant, inflamed tissue or tissue that is otherwise different from normal or healthy tissue, by applying a modulated signal (4) to the affected tissue, where the modulated signal (4 ) is capable of selectively increasing the temperature or heating the affected tissue, while in the surrounding healthy tissue there is no direct temperature increase or heating by means of the supplied RF waves.

The frequency modulation of the source signal (8) by the modulating signal generator (13) has the following advantages:

1. The functions of exchanging information about health according to the well-known fact from the fractal physiology of the dynamics of healthy biological processes that long-term fluctuations in entropy are equal in all areas. Energy absorption in areas other than pink noise will be higher than in areas with pink noise. In the pink areas, on the other hand, social signaling will be reliably ensured. Thus, heating occurs selectively only in areas not with pink noise.

2. Modulation increases the gradient of the electric field in the extracellular fluid, which builds large protein molecules. Modulation performs a frequency distribution around the carrier frequency (13.56 MHz, see FIG. 28), which increases the amplitude (electric field) in this region. This order makes the social signal available (induction of apoptosis) and “glues” dividing cells in a fixed position (metastatic block).

As described above, the density of the electric current is concentrated in the extracellular electrolyte, and also due to beta dispersion on the membrane, the specific absorption coefficient (UKP) is of high value. An inhomogeneous force field is created perpendicular to the cell membrane (see Fig. 19). This field (E) creates a dielectrophoretic cataphoretic force (F) according to formula (A) (see Fig. 18), the molecules have a dipole moment p:

F = ( p × grad) E Formula (A).

The cataphoretic forces (well-oriented domains, dimers) of such large molecules as E-cadherin on the membrane surface allow them to bind again (see Fig. 20), thus connecting the dimers to each other. The gradient inside the cell leads to the orientation of beta-catenins and other anchor proteins (e.g., catenin p120) to connect with actin or a network of cell filaments.

The electric field causes three effects (see Fig.21):

1) stimulates the binding of unconnected adhesins (decrease in the dissociation reaction constant k _D ),

2) an increase in activation energy (threshold E ₀ ) and a decrease in the dissociation reaction constant k _D ,

3) the creation of an attractive force between closely spaced membranes (a decrease in the force f of a single bond).

In the compounds formed, the field lines are drawn by cadherins, which have an extremely high relative permeability (sometimes several thousand) (see FIG. 22). In turn, this creates “hot spots” on the membrane and stimulates membrane damage.

The effect of promoting sticky compounds is directly opposed to dissociation caused by fever. Thus, there is a clear difference between oncothermia and classical methods of heat treatment.

Regarding modulation, modulation can act effectively on pain receptors, thus helping to suppress pain in a malignant tumor (a typical effect of percutaneous electrical nerve stimulation).

Modulation of pink noise is preferred, but the pink noise spectrum is not mandatory in all cases.

The combination of modulating the frequency of the source signal (8) with a feedback signal (5) and modulating the frequency of the source signal (8) with a modulating signal generator (13) provides the following advantages:

1. The feedback signal makes it possible to use strong or weak modulation as necessary, thus individualizing the energy delivered to the target tissue in real time. Patients and tumors have personality and have their own specific impedance. The electric circuit, of which the patient is a part (the patient is a capacitor with installed electrodes), is optimized in each simple case for the actual impedance, and also corrected for its changes during exposure.

2. The feedback signal allows the use of the Chelomei (Kapitsa) effect to stabilize the mechanisms of deformation and optimize the destruction of malignant cells.

Thus, the present invention relates to an RF device for hyperthermia, which comprises an RF source (1), an amplifier (2), a sensor (3), a feedback amplifier (6) and a modulating signal generator (13), where the RF source generates a source signal (8), which is modulated by a modulating signal generator (13) to generate a modulated source signal (10), the modulated source signal (10) is amplified by an amplifier and sent to the target (17), and the sensor receives a feedback signal link (5) from the target that is directed to the feedback amplifier, wherein the feedback signal is amplified by the feedback amplifier and modulates the source signal to generate a target modified modulated signal (4).

Preferably, the feedback signal (5) modulates the modulating signal from the modulating signal generator (13). In addition, preferably, the source signal (8) is modulated by a modulating signal from a modulating signal generator (13), which is modulated by a feedback signal (5). Preferably, the modulating signal generator (13) is a pink noise generator. Preferably, the sensor (3) is placed between the amplifier (2) and the target (17) or, alternatively, the sensor (3) is placed between the target (17) and the feedback amplifier (6). Preferably, the amplitude and frequency spectrum of the source signal are modulated.

The preferred frequency for use in the present invention is in the range of all frequencies that are capable of modulating the carrier frequency, typically up to a tenth of the carrier frequency. The most preferred is the sound range of 5-20000 Hz, since the resonant effects of biological systems lie in the sound range.

The preferred power for use in the present invention is in the range from 30 to 1500 watts. Most preferred is a range of 60-250 watts. In particular, this range is safe and provides sufficient power to heat damage. The volume of the tumor (in the case of large tumors) does not exceed the volume of 1 liter. Even 250 watts will be too much to heat it from body temperature to 40-45 ° C (with a gradient of less than 10 ° C per hour). This is provided only for the case of rich vascularization of the tumor, which can lead to a significant effect of blood cooling.

The hyperthermia device of the present invention may be a device for transferring energy with coupling through an electric field (device with capacitor coupling), a device for transferring energy with coupling through a magnetic field (device with inductive coupling), or a device for transferring radiated energy (device with coupling by radiation or with an antenna array). Preferably, the radio-frequency hyperthermia device of the present invention is a hyperthermia device for transferring energy with coupling through an electric field (capacitor coupled device).

A preferred device also has an applicator electrode. The applicator electrode may be a conventional disk electrode, where the active electrode is paired with a counter electrode, and the target tissue is placed between the active electrode and the counter electrode. Alternatively, the applicator electrode may be an electrode structure that selectively delivers energy only to surface tissues, the applicator contains several positive and negative electrodes provided alternately in the applicator. Two possible examples of suitable designs with alternating positive and negative electrodes are a matrix arrangement (checkerboard) of alternating positive and negative electrodes or an arrangement in the form of concentric rings of alternating positive and negative electrodes. This design can be used with or without a conventional disk, and it does not require the use of an opposed counter electrode.

Or, in addition, alternatively, the applicator electrode may be a non-disk type flexible electrode. The flexible electrode may be in the form of a belt or bandage with a zipper. For example, it may be in the form of a belt and contain paired electrodes, for example, one pair or two pairs of capacitive electrodes. Instead of a coated flexible carrier or coated flexible material, a conductive metal network or a conductive metal mesh made of at least one conductive metal electrode material can be used. Such metal nets or metal nets preferably do not contain any framework, such as a polymer mesh structure. The metal network or mesh is preferably a woven structure of metal fibers that has properties very similar to a coated flexible material, such as a coated fabric. A conductive metal network or mesh is flexible, allows water and other liquids and gases to pass through, it can be bent without negatively affecting electrical conductivity, and it can be coated with non-smooth, fractal and / or percolation surfaces. Thus, metal networks and grids of all types, having the above properties of conductively coated materials, such as conductively coated fabrics, can be used in the proposed tool for transferring electromagnetic energy. The conductive metal coating is a multilayer coating. Preferably, one of the layers is silver, which has a good antibacterial effect and provides good radio frequency (RF) conductivity. In addition, silver has an anti-odor effect along with a moderate effect of reducing perspiration. Therefore, silver is preferred for cosmetic, medical, and health products. However, other conductive metal coatings may also be used. The resulting flexible material with a conductive metal coating remains porous enough to allow the exchange of heat and fluids.

Another aspect of the present invention is the use of the proposed radio frequency (RF) device for hyperthermia to provide an improved method for selectively affecting a localized target site. The proposed device for hyperthermia, in particular, can be used to treat pain, cancer, solid tumors, as well as metastases of malignant tumors.

Thus, the hyperthermia device of the present invention can be used to selectively target a localized target site, where the localized target site is selected from tumor tissues and muscle tissue or organs such as, for example, liver, lung, heart, kidney, spleen, brain , ovary, uterus, prostate, pancreas, larynx, gastrointestinal tract and gynecological tract.

Tumor tissue can be selected from adenocarcinoma, choroidal melanoma, acute leukemia, acoustic neuroma, ampullary carcinoma, anal carcinoma, astrocytoma, basal cell carcinoma, pancreatic cancer, desmoid tumor, malignant bladder cancer, lung cancer, LC, ), a malignant tumor of the breast, Burkitt’s lymphoma, a malignant tumor of the body, CUP syndrome (carcinoma of unknown origin), colorectal malignant a tumor, a malignant tumor of the small intestine, a tumor of the small intestine, a malignant tumor of the ovary, endometrial carcinoma, ependymoma, malignant tumor of the epithelial type, Ewing tumor, a tumor of the gastrointestinal tract, a malignant tumor of the stomach, a malignant tumor of the gallbladder, carcinoma of the gall bladder, malignant uterus, malignant tumor of the cervix, glioblastoma, tumors of the gynecological tract, tumors of the ear, nose and throat, hematological neoplasms, hairy cell leukemia, a malignant tumor of the urethra, a malignant tumor of the skin, a malignant tumor of the skin of the testicles, brain tumors (gliomas), metastases in the brain, a malignant tumor of the testicles, a tumor of the pituitary gland, carcinoids, Kaposi’s sarcoma, a malignant tumor of the larynx, a tumor from the germ cells, tumors of bone, colorectal carcinoma, tumors of the head and neck (tumors of the ear, nose and throat), colon carcinomas, craniopharyngiomas, malignant tumors of the oral cavity (malignant tumor in the mouth and on the lips), a malignant tumor of the central nervous system, a malignant tumor of the liver, liver metastases, leukemia, a tumor of the eyelid, a malignant tumor of the lung, a malignant tumor of the lymph node (Hodgkin / non-Hodgkin), lymph, a malignant tumor of the stomach, malignant melanoma, malignant neoplasm, malignant tumors of the gastrointestinal tract, breast carcinoma, malignant tumor of the rectum, medulloblastoma, melanoma, meningioma, X disease ojkina, fungoid mycosis, malignant tumor of the nose, neuroma, neuroblastoma, malignant tumor of the kidney, renal cell carcinoma, non-Hodgkin lymphoma, oligodendroglioma, carcinoma of the esophagus, osteolytic carcinoma and osteoplastic carcinoma, osteosarcoma ovary carcinoma, carcinoma ovum carcinoma plasmacytoma, squamous cell carcinoma of the head and neck (SCCHN), malignant tumor of the prostate gland, malignant tumor of the pharynx, carcinoma of the rectum, retinoblas volumes, cancer of the vagina, thyroid carcinoma, Schniberger disease, cancer of the esophagus, spinalomas, T-cell lymphoma (fungoid mycosis), thymoma, carcinoma of the duct, eye tumors, cancer of the urethra, urological tumors, urothelial carcinoma, external genitalia, the occurrence of warts, soft tissue tumors, soft tissue sarcoma, Wilms tumor, cervical carcinoma and a malignant tumor of the tongue. Particularly suitable for treatment are, for example, astrocytomas, glioblastomas, a pancreatic cancer, a bronchial cancer, a breast cancer, a colorectal cancer, an ovarian cancer, a gastric cancer, a laryngeal cancer, a malignant tumor, a food tumor cancer of the cervix uteri, cancer of the liver, cancer of the bladder and cancer of the cell renal epithelium.

The hyperthermia device of the present invention can be used in combination with chemotherapeutic treatment using cytostatic and / or cytotoxic drugs. An example of some cytostatic and / or cytotoxic drugs are actinomycin D, aminoglutethimide, amsacrine, anastrozole, purine and pyrimidine base antagonists, anthracycline, aromatase inhibitors, asparaginase, antiestrogens, bexarotene, campelecinutenec, bucetelecinothecin, busulentinecin, carcinofin, carcinogen, bucetelecinomecin, baculentinecin, carboxynecin-aminobenzenecin , chlorambucil, cisplatin, cladribine, cyclophosphamide, cytarabine, cytosine arabinoside, alkylating cytostatic agents, dacarbacin, dactinomycin, daunorubicin, docetaxel, doc orubicin (adriamycin), doxorubicin lipo, epirubicin, estramustine, etoposide, exemestane, fludarabine, fluorouracil, folic acid antagonists, formestane, gemcitabine, glucocorticoids, göselen, hormones and antagonists of hormones, gimincinofin aminofin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinfin aminocinf aminocin and aminocinfin aminocinfin aminocinfin aminocin that , leuprorelin, lomustine, melphalan, mercaptopurine, methotrexate, miltefosine, mitomycin, mitosis inhibitors, mitoxantrone, nimustine, oxaliplatin, paclitaxel, pentostatin, procarbacin, tamoxifen, temozolomide, teniposide, testolactone, testolactone thioguanine, topoisomerase inhibitors, topotecan, threosulfan, tretinoin, triptorelin, trophosphamide, vinblastine, vincristine, vindesine, vinorelbine, antibiotics with cytotoxic activity. All current and future cytotoxic or other drugs, including gene therapy, can be used.

When using the hyperthermia device of the present invention to treat inflammatory conditions, it can be used in combination with treatment with anti-inflammatory drugs, such as non-steroidal anti-inflammatory drug (NSAID), such as alkofenac, aceclofenac, sulindac, tolmetin, etodolac, phenoprene, thiaprofenic acid, meclofenamic acid, meloxicam, tenoxicam, lornoxicam, nabumetone, acetaminophen, phenacetin, ethenzamide, sulpirin, mefanamic acid, flufenamic acid, diclofenac sodium, loxoprofen sodium, phenylbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen, fenbufen, pranoprofen, floctafenin, piroxicam, epirizole, tiaramide hydrochloride, coltatcinfenfrostin-moprofin, m-colofenfencitrofen, m-colofenfencitrofen, m-colofenfencitrofen, m-colofin , allopurinol, salicylic acid, atropine, scopolamine, levorphanol, ketorolac, tebufelon, tenadap, clofeson, oxyphenbutazone, prexazone, apazone, benzidamine, bucol, kinhopen, clonixin, dithrazole, epirizole, phenoprofen, flokta Enin, glafenin, indoprofen, niflumic acid and suprofen, or with the use of steroidal anti-inflammatory drugs such as dexamethasone, hexestrol, methimazole, betamethasone, triamcinolone, fluocinonide, prednisolone, methylprednisolone, hydrocortisone, fluorometholone, beclomethasone dipropionate, estriol, clobetasol, diflorasone diacetate , galbetosal, amicinonide, deoxymethasone, galciononide, mometasone furoate, fluticasone propionate, fluradrenolide, clocortalon, predincat, aclomethasone dipropionate and desonide.

Another aspect of the present invention is the use of the proposed device for hyperthermia to provide an improved method of treating hyperthermia for diseases of the upper respiratory tract. Infections of the upper respiratory tract are caused by viruses and bacteria in which the temperature of optimal growth and survival is lower than the internal temperature of the body. Therefore, these infections can also be treated using hyperthermia treatment. For example, the positive effect of the use of heat in bacterial infections of the upper respiratory system (for example, with a common cold) is well known. The mucosa has a high conductivity. Like tumor tissue, concentration of the heat effect also occurs (as in the treatment of asthma). Thus, the proposed method has increased selectivity with a common cold compared with other methods of heating. Thus, the hyperthermia device of the present invention can also be used to treat rhinitis and other infections of the upper respiratory tract. Examples of viruses that cause upper respiratory tract infections are rhinoviruses, coronaviruses, adenoviruses, myxoviruses, coxsackie viruses, echoviruses, parainfluenza viruses, respiratory syncytial viruses and influenza viruses. Examples of bacteria that cause upper respiratory tract infections are Mycoplasma pneumoniae, Chlamydia pneumoniae, Streptococcus pneumoniae, Corynebacterium diptheriae, and Haemophilus influenzae.

Another aspect of the present invention is the use of the proposed device for hyperthermia to provide an improved method of treating hyperthermia for the treatment of pain. In these cases, treatment can be carried out at normal body temperature or at least so that the temperature increase in the target tissue is negligible.

Another aspect of the present invention is a method of modulating a signal of a radio frequency device that comprises a radio frequency source (1) that provides a source signal (8), an amplifier (2), a sensor (3), a feedback amplifier (6) and a modulating signal generator ( 13), which includes the stages:

modulating a source signal (8) using a signal from a modulating signal generator to generate a modulated source signal (10),

amplification of a modulated source signal (10) using an amplifier,

sending a signal to the target (17),

receiving a feedback signal (5) from the target by means of a sensor,

sending a feedback signal to the feedback amplifier,

feedback signal amplification using a feedback amplifier,

the feedback signal modulates the signal from the modulating signal generator (13), and

modulating a source signal using a modulated signal from a modulating signal generator to generate a modulated source signal (4).

Description of drawings

Figure 1 shows a radio frequency device of the prior art.

Figure 2 shows a prior art RF device with several parallel channels that can be adjusted for modulation without feedback from the target tissue.

Figure 3 shows an embodiment of the present invention with a modulating signal generator (13) and without a feedback amplifier (6).

Figure 4 shows an embodiment of the present invention without a modulating signal generator (13) and with a feedback amplifier (6).

5 shows an embodiment of the present invention with a pink noise generator as a modulating signal generator (13) and a feedback amplifier (6).

FIG. 6 shows in detail an embodiment of the present invention, as shown in FIG. 5, with a feedback sensor in a first position (1).

FIG. 7 shows in detail an embodiment of the present invention, as shown in FIG. 5, with a feedback sensor in a second position (2).

On Fig shows a joint culture of normal fibroblasts of human skin and cells of aggressive squamous cell carcinoma A431 (cell line malignant melanoma), which were treated using the device of the present invention (labeled "oncothermia").

Figure 9 shows the cell line of acute human promyelocytic leukemia HL60, which was treated using the device of the present invention.

Figure 10 shows a co-culture of normal healthy human fibroblasts and cells of aggressive squamous cell carcinoma A431, which were treated using the device of the present invention (labeled "oncothermia"), compared with cells that were treated using a conventional device for hyperthermia (labeled "hyperthermia" ").

11 shows the measured maximum expiratory flow rate (MOSV in l / s) and forced expiratory volume in 1 second (FEV1 in l) [Spirometry] at 7 points in time.

12 shows the measured maximum expiratory flow rate (MOSV in l / s) and forced expiratory volume in 1 second, (FEV1 in l) [Spirometry] at 4 points in time.

13 shows an example of a modulated signal.

FIGS. 14A and B. FIG. 14A shows the amplitude modulated signal, and FIG. 14B shows the demodulated signal of FIG. 14A by cutting off only the symmetrical portion of the modulated signal of FIG. 14A.

15 shows environmental noise (white noise).

16A and B show how a small deterministic signal is mixed (modulated or simply summed) with noise. Signal strength is much less than noise power. The difference between FIGS. 16A and 16B is that two deterministic signals (one high frequency and one low frequency) are added to the same white noise spectra.

Figa and B relate to demodulation, a process with a specific ratio of threshold and noise. (Either the threshold is changed using a fixed noise amplitude, or the noise amplitude is changed using a fixed sensitivity threshold). On figa and 17B shows that both [low-frequency (17A) and high-frequency (17B)] deterministic signals can be "demodulated" by stochastic resonance.

On Fig shows an electric field (E), which creates a dielectrophoretic cataphoretic force (F) on a biological molecule, such as E-cadherin, with a dipole moment p.

Fig. 19 shows that, due to the electric field (E), a dielectrophoretic cataphoretic force (F) develops, and due to the dipole moment p of the molecule perpendicular to the cell membrane, an inhomogeneous force field develops.

On Fig shows that cataphoretic forces allow dimers of E-cadherin on the surface of the membrane to communicate with each other, thus connecting the dimers with each other.

In Fig.21 shows that the electric field (E) creates attractive forces between adjacent membranes of two cells.

On Fig it is shown that in the established compounds the field lines are drawn by cadherins, which have an extremely high relative permeability, which creates hot spots on the membrane and contributes to damage to the membrane.

On Fig shows the "formation" of the Kapitza equation.

On Fig shows the frequency dependence of the permeability of Debye.

25 shows a high frequency lossy capacitor control. E (t) refers to the field strength of the carrier frequency, and g (j) f (t) refers to the field strength depending on the density of the high-frequency current.

On figa and B presents a macroscopic temperature measurement (Luxtron sensor, figa) and microscopic (subcellular activity of luciferase, figv) comparison of temperature when measuring hyperthermia and oncothermia in the cell line HEK293, temporarily transfected using Luc-GFP.

On Fig shows an improvement in the reduction of pain during treatment with hyperthermia. Patients subjectively evaluated the strength of pain before and after treatment with hyperthermia in 48 patients.

On Fig shows the modulation, which carries out the frequency distribution around the carrier frequency (13.56 MHz), which increases the amplitude (electric field) in this area.

EXAMPLES

Example 1

A joint culture of normal human skin fibroblasts and aggressive A431 squamous cell carcinoma cells (malignant melanoma cell line) as a model of squamous cell carcinoma growing in connective tissue cells was treated using the device of the present invention (marked “oncothermia”) for 30 minutes at 42 ° C. The temperature was accurately determined using Luxtron fluoroscopic sensors, which do not contain metal components near the sample. Due to the importance of temperature as a control for standardized exposure, the macroscopic temperature must be equal to the microscopic temperature. Microscopic (subcellular) temperature was confirmed by transfected luciferase (as a molecular thermometer). The HEK293 cell line was used as a model. Carried out a joint transfection of luciferase and GFP, which does not have temperature sensitivity, as a reference. Macroscopic and microscopic temperature measurements are shown in figa and 26B. Identity is required.

Also, all comparative studies were carefully carried out in dynamics. The samples not only maintained a constant temperature, but also controlled the dynamics of heating and cooling and maintained equivalence, therefore, they maintained a strict identity of the steepness of heating and cooling (see Fig. 26A). Subsequently, the culture was incubated for 24 hours at 37 ° C, fixed and stained with crystal violet. Cell selectivity was observed after treatment. Malignant cells were destroyed, and healthy fibroblasts remained intact, as shown in Fig. 8.

Example 2

Similar selectivity was demonstrated on the HL60 leukemia cell line (acute human promyelocytic leukemia cell line in cell suspension culture, RPMI-1640, 10% FBS). HL60 leukemia cell culture was treated using the device of the present invention (labeled “oncothermia”) for 30 minutes at 42 ° C. (see above) compared to HL60 leukemia cells that were treated using a conventional hyperthermia device (labeled “hyperthermia” ”) For 30 minutes at 42 ° C (see above). When comparing a conventional device and the proposed device, the heating of the cells is identical. However, the results obtained by the proposed device (cell number: 18000 cells / ml after treatment), significantly improved compared to a conventional device (cell number: 25000 cells / ml after treatment), as shown in Fig.9.

Example 3

A co-culture of healthy human fibroblasts and A431 squamous cell carcinoma cells growing in normal human skin fibroblast cells (100,000 / ml) was treated using the device of the present invention (labeled “oncothermia”) for 30 minutes at 42 ° C (see above ) compared with similar cells that were treated using a conventional device for hyperthermia (labeled "hyperthermia") for 30 minutes at a temperature of 42 ° C (see above). Subsequently, the culture was incubated for 24 hours at a temperature of 37 ° C. Success was measured by the appearance of beta-catenin in time after treatment, as shown in FIG. 10.

Example 4

An apoptosis / necrosis experiment was performed on a x29 transplant model of human HT29 colorectal carcinoma in nude mice. Mice were treated using the proposed device for 30 minutes at a temperature of 42 ° C (see above) compared with a conventional device for hyperthermia for 30 minutes at a temperature of 42 ° C (see above). Using the in situ Roche cell death kits kit, DAPI (staining of double-stranded DNA only) and Tunel-FIC (enzymatic labeling of DNA strand breaks) were stained. After treatment using a conventional device for hyperthermia, cell death was observed mainly in the form of necrosis, whereas after treatment using the proposed device for hyperthermia, cell death was observed mainly in the form of apoptosis.

Example 5

Pain treatment was carried out in 48 patients suffering from glioma (12 patients), rheumatic pain (17 patients), migraine (10 patients), joint pain (9 patients). The treatment was performed using an electrode with a diameter of 30 cm for treating the chest, a diameter of 10 cm for treating the head and a diameter of 7 cm for treating knees that were placed on the chest, back, head or knee of the patient. The treatment was carried out three times a week (every two days) for a month, and before and after each treatment, patients were asked to rate their strength of pain on a scale of 1 to 10, where 1 indicates no pain and 10 indicates incredible pain. A power of 150 W was used for 1.5 hours with a step-by-step increase (starting from 80 W, the power was increased to 150 W with 5 min intervals and a step of 20 W (the last step was 10 W)). The total energy transferred was approximately 780 kJ.

The results of the treatment of pain are shown in Fig.27. A very favorable result was that one third of all patients with acute pain (score from 7 to 10) before treatment with hyperthermia reported the disappearance of pain after treatment.

Example 6

The effect of the proposed treatment of patients with obstructive pulmonary diseases was carried out on a limited number of patients to provide treatment for acute or chronic allergic rhinitis, asthma, and upper respiratory tract infections.

The total number of patients included in the study and evaluated was 19, the patients were divided into 3 groups:

- patients with chronic obstructive bronchitis (5 patients),

- bronchial asthma (III-IV degree for more than 10 years) (11 patients),

- bronchial asthma (I-II degree for no more than 2 years) (3 patients).

The initial state and progress of patients were measured by tests of respiratory function, testing with a peak flow meter (twice a day) and a survey of the subjective state of patients (in accordance with accepted standards) + patient diaries during treatment.

The treatment was performed using an electrode with a diameter of 30 cm, which was placed on the chest of the patient. The treatment was carried out three times a week (every two days) for a month, followed by a follow-up period. A power of 150 W was used for 1.5 hours with a step-by-step increase (starting from 80 W, the power was increased to 150 W with 5 min intervals and a step of 20 W (the last step was 10 W)). The total energy transferred was approximately 774.6 kJ.

The authors of the present invention concluded that the treatment of hyperthermia using the proposed device has beneficial effects on patients undergoing treatment, in that their lung function parameters became better and their subjective well-being was significantly better.

The authors of the present invention measured the maximum volumetric expiratory flow rate (MOSV) and forced expiratory volume in 1 second, (FEV1) [Spirometry]. The most promising signs were observed in the group of patients with bronchial asthma (III-IV degree) with severe and serious symptoms, where in the case of 7 patients the value of MOSV increased by more than 25%. 10 patients out of 11 recognized their general subjective state as definitely improved, only 1 patient reported a worse subjective state.

Two cases reported:

A patient: woman, 57 years old Condition: bronchial asthma was diagnosed in 1996, grade III-IV, Treatment used: - Serevent rotadisk
- Pulmicort 400 mcg turbuhaler
- Spray Ventolin

Results:

Date / Measurement 09/04/2000 10/03/2000 03/21/2001 05/02/2001 06/06/2001 07/05/2001 08/07/2001 FEV1 [l] 1.92 2.12 1.94 2.01 1.97 1.9 1.7 MOSV [l / s] 3,58 7.17 5.36 6.61 5,6 5.77 4.28 Only Ventolin treatment was used.

The results are shown in Fig.11.

Summary of these results:

- after the third treatment, the expectorant disappeared, first yellowish, then white,

- the general condition of the patient has improved,

- increased patient activity,

- reduced previously prescribed doses of drugs, later only Ventolin was used,

- bronchodilators used only in rare cases,

- probably the improvement is permanent.

Two cases reported:

A patient: woman, 55 years old Condition: bronchial asthma was diagnosed in 1993, IV degree The patient suffered from: - diabetes
- osteoporosis,
- hypertension. Treatment used: (in addition to the treatment of diabetes mellitus, hypertension and osteoporosis): - Pulmicort 400 mcg turbuhaler,
- Theospirex 300 mg,
- Medrol 8 mg / day,
- Berodual solution for inhalation + spray.

Results:

Date / Measurement 10/10/2000 11/20/2000 03/13/2001 07/25/2001 FEV1 [l] 0.98 1.42 1.36 1.15 MOSV [l / s] 2.06 3.66 3.00 2.91 Steroid treatment was canceled. For treatment, only Pulmicort was used.

The results are shown in Fig. 12.

Summary of these results:

Of the seven patients, respiratory function increased in five, remained unchanged in two, at least 22% of significant changes in the patient's condition (the most significant change was three times higher than the initial state). In two patients "without changes" acute catarrhal exacerbation.

Conclusion on non-cancer cases involving the respiratory tract and treatment:

- after the third treatment, the expectorant disappeared, first yellowish, then white,

- reduction or elimination of dyspnea,

- elimination of bronchial obstruction, bronchial mucosa passes,

- improving the general condition of the patient,

- increased patient activity,

- reduced previously prescribed doses of drugs, later only Ventolin was used,

- bronchodilator used only in rare cases,

- probably the improvement is permanent,

- treatment was well tolerated, no side effects were observed.

Claims (13)

1. An RF device for hyperthermia with capacitive coupling and without a dipole antenna and without a phased array, which contains an RF source (1), an amplifier (2), a sensor (3) and a modulating signal generator (13), in which the RF source generates a signal (8) a source that is modulated by a modulating signal generator (13) to generate a modulated source signal (10), wherein the modulated source signal (10) is amplified by an amplifier (2) and sent to the target (17), and the sensor receives cash (5) feedback from the target, the signal (5) modulates the feedback signal (8) a source for generating a target modified modulated signal (4). 2. The radio frequency device according to claim 1, which further comprises a feedback amplifier (6) for amplifying the feedback signal (5). 3. The RF device according to claim 1, wherein the feedback signal (5) modulates the modulating signal from the modulating signal generator (13). 4. The radio frequency device according to claim 1, wherein the source signal (8) is modulated by a modulating signal from a modulating signal generator (13), which is modulated by a feedback signal (5). 5. The RF device according to claim 1, wherein the modulating signal generator (13) is a pink noise generator. 6. The radio frequency device according to claim 1, in which the sensor (3) is placed between the amplifier (2) and the target (17). 7. The radio frequency device according to claim 1, in which the sensor (3) is placed between the target (17) and the feedback amplifier (6). 8. The radio frequency device according to claim 1, in which the amplitude and frequency spectra of the source signal are modulated. 9. The radio-frequency device for hyperthermia according to claim 1, wherein the device is selected from a device for transferring energy with communication through an electric field, a device for transferring energy with communication through a magnetic field, or a device for transferring radiated energy. 10. The use of a radio frequency device, as defined by any one of claims 1 to 9, for the treatment of hyperthermia. 11. Use for hyperthermia a modulating feedback circuit containing a feedback amplifier (6) for amplifying a feedback signal (5), a sensor (3) for detecting a reflected or transmitted signal from a target (17), a modulating signal generator (13) for modulating or additional modulation of the feedback signal (5) and for generating a modulating signal (12) for forming a radio-frequency device for hyperthermia according to any one of claims 1 to 9, which can be used for the prevention, treatment and subsequent treatment of tumors, malignant thyroid tumors, metastases, carcinomas, pain, migraines, and central nervous system disorders. 12. The use according to claim 11, in which the modulating feedback circuit further comprises a modulator (9) for receiving a modulating signal (12) from the modulating signal generator (13). 13. A method of modulating a signal of a radio frequency device that contains a radio frequency source (1) that provides a source signal (8), an amplifier (2), a sensor (3), a feedback amplifier (6) and a modulating signal generator (13), including self stages:
modulate the source signal (8) with a signal from the modulating signal generator to generate a modulated source signal (10), amplify the modulated source signal (10) with an amplifier, direct the signal to the target (17),
receive a sensor signal (5) feedback from the target,
direct the feedback signal to the feedback amplifier,
amplifying the feedback signal with a feedback amplifier, modulating the feedback signal from the modulating signal generator (13), and
modulate the source signal with a modulated signal from a modulating signal generator to generate a modulated source signal (4).

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