MXPA00010253A - Detection of cancerous lesions by their effect on the spatial homogeneity of skin temperature - Google Patents

Abstract

The present invention comprises methods for cancer detection involving the measurement of temporal periodic changes in blood perfusion, associated with immune response, occurring in neoplastic lesions and their surrounding tissues. Particularly, the method for cancer detection involves the detection of non-neuronal thermoregulation of blood perfusion, periodic changes in the spatial homogeneity of skin temperature, aberrant oscillations of spatial homogeneity of skin temperature and aberrant thermoregulatory frequencies associated with periodic changes in the spatial homogeneity of skin temperature.

Description

DETECTION OF CANCERING INJURIES BY ITS EFFECT ON THE SPACE HOMOGENEI DAD OF THE SKIN TEMPERATURE CROSS REFERENCE TO RELATED REQUEST The present application is a continuation in part of the serial request no. 08/368, 161, filed on January 3, 1995.

ANTECEDENTS OF THE TECHNIQUE FIELD OF THE INVENTION The present application relates generally to the detection of cancer which involves the measurement of temporal periodic perfusion changes associated with the immune response in tissue surrounding cancerous lesions. Although this has applications of cancer detection throughout the human body, it is particularly applicable to a breast cancer screening test involving measurement of temporary changes in perfusion over large areas of the sinuses to identify cancer. In general, a complete examination, such as an ultrasonic scan, incisional or needle biopsy, or stereotactic biopsy based on a detailed mammographic image, is preceded by a positive finding in a breast cancer screening test. The present invention has many significant differences and advantages over breast cancer screening tests known in the art, as well as methods of detecting cancer in general.

BACKGROUND ART Cancer lesions have been generally located by their space-occupying properties detectable by palpation or by imaging techniques, such as X-ray radiography, X-ray computed tomography (CT), ultrasonic imaging, or imaging. of magnetic resonance (MRI). In certain cases, such as breast cancer, the detection of cancer is made possible by the intensified blood supply (hyperperfusion) associated with the neoplastic lesion. In shallow lesions, such as breast cancer, this hyperperfusion results in local hyperthermia. The hyperthermia of cancerous breasts has been used to detect breast cancer. In classical thermal imaging (thermography), the skin temperatures of both sinuses are measured either by liquid crystal contact thermography (LCCT) or by infrared imaging. The volume temperatures of both breasts is also measured by microwave telethermometry. The difference between the temperatures of the cancerous sinus and the non-cancerous breast is often not identified as a signal for additional cancer testing, since the temperature difference is very similar to different between two non-cancerous sinuses. Temperature differences can occur for a variety of reasons unrelated to the presence of cancer. Therefore, the sensitivity and specificity of breast cancer detection by such temperature measurements are too low to make them useful as a practical classification test. The present invention does not use differences between the temperatures of the two sinuses as a diagnostic criterion. X-ray mammography (XRM) is a widely used technique to classify breast cancer before complete diagnostic tests. It uses the highest density of calcium minerals and the highest absorbance of X-rays in calcium atoms, due to the photoelectric effect, to detect the microcrystals of calcium minerals, usually calcium phosphate, which are deposited interstitially in the cancerous tissue. The characteristic shadow of the relatively opaque microcrystals of calcium minerals in the radiograms indicate their presence in the tissue. A disadvantage of XRM as a breast cancer screening test is the occurrence of microcalcification or calcification in benign lesions, hence only a fraction of sinuses that manifest microcalcification contain malignant tissue. False positive XRM results are common, and lead to complete diagnostic tests, which often prove negative for breast cancer. The present invention does not use calcification or microcalcification of tissue as a diagnostic criterion. Because pathological microcalcification occurs subsequent to the formation of a tumor, it happens later to the proliferation of cancer cells, which produces nitric oxide, and the immune response to neoplastic cells, which invokes the activity of macrophages that also produce nitric oxide. Accordingly, the detection of breast cancer by XRM occurs subsequent to detection by the present invention.

In addition, the present invention is significantly less expensive than XRM. The equipment required for the present invention costs less than one third the cost of XRM equipment. The installation required for the present invention is substantially less expensive (radiation protection with XRM is required), the personnel necessary for the method of the present invention requires substantially less training and is not exposed to any professional hazard (ionizing radiation). Moreover, the present invention does not require an image recognition from an expert, while XRM requires the expertise of a radiolt. Accordingly, the actual cost of the present invention is significantly less than the cost of XRM. A cost / benefit analysis shows that even if the sensitivity and specificity of the test of the present invention equals those of XRM, the present invention is more beneficial, even on purely economic grounds. Additionally, the present invention has zero risk to the patient. On the contrary, even with the use of modern mammography equipment, there is a limited risk of cancer induction by XRM. The risk is at least 1 in 1, 000,000 tests, and more likely it is substantially higher. In addition, the present invention causes much less discomfort to the patient than the squeezing of the breasts that must be done in a suitable mammography. The current sensitivity and specificity of XRM are far from satisfactory, especially in flat sinuses and dense breasts. The present invention is substantially more sensitive and specific than classical thermal imaging, (which was shown to be only slightly less effective than XRM), and therefore, is superior to XRM in diagnostic efficiency. Unlike XRM, which is dependent on microcalcification to make the tumor detectable, the present invention directly detects cancer cells and the immune response to them and, consequently, detects breast cancer substantially before XRM. Because the outcome of breast cancer treatment is more favorable the earlier the cancer is detected, the present invention has a substantial advantage over XRM in improving public health. 1 . Dynamic area telethermometry Dynamic area telethermometry (DAT) is a concept known and fully described in the 1 991 application of Dr. Michael Anbar, Thermology 3 (4): 234-241, 1991. However, there is no known practical application for DAT in the public domain. It is a functional, non-invasive test of the autonomic nervous system, which monitors changes in the spectral structure and spatial distribution of thermoregulatory frequencies (TRFs) over different areas of human skin. Based on the science of infrared radiation, as measured by infrared imaging, DAT derives information on the dynamics of heat generation, transport and dissipation from changes in the temperature distribution over areas of interest. Changes can be detected in the average temperatures of area segments or variations in those averages; the variations measure the homogeneity of the temperature distribution, and therefore, the homogeneity of the skin perfusion. As shown by Dr. Anbar in European J Thermology 7: 1 05-1 1 8, 1 997, under conditions of hyperperfusion, the homogeneity reaches a maximum and the amplitude of its temporal modulation is at a minimum. From the periodic changes in the temperature distribution over different areas of skin, the thermoregulatory frequencies of the processes that control the temperature in the given areas can be derived. From the periodic changes in the spatial homogeneity of the skin temperature (HST), the processes that control the saturation of the cutaneous capillary bed can be derived. HST is the reciprocal of the spatial coefficient of temperature variation in small ("micro") areas of the skin (<; 100 mm2): HST = average temperature divided by the standard deviation of the average temperature (HST is a dimensionless parameter). HST is determined by the cutaneous vasculature structure and by its heat dissipating activity. As the perfusion intensifies, more capillaries are recruited as blood conduits and the HST increases. Unlike the average temperature, HST is affected mainly by the behavior of the cutaneous capillaries and to a much lesser extent by the blood flow in the subcutaneous vessels. The neuronal control of HST is different, therefore, from that of the skin temperature. Consequently, HST is an independent physiological hemodynamic parameter. As the average temperature of skin unit areas, HST oscillates as a function of the temporal behavior of the perfusion. Because the rate of increase in HST with the degree of perfusion is much greater than that of temperature, the degree of its change and the amplitude of its modulation are significantly greater than those of temperature change and temperature modulation. A static image of HST is, therefore, more informative than a classical thermogram. The concept of HST has been fully described by Dr. Michael Anbar in Biomedical Thermology, 1 3: 1 73-1 87, 1994. Quantitative DAT requires high precision measurements of the infrared flow (corresponding to <0.01 ° C), low instrumental and electronic noise (<0.0005 ° C equivalent of electronic or thermal noise), and long-term stability (deviation of <0.1 ° C / h). All of these can be obtained with current commercial equipment. The minimum resolution required for DAT is an image field of 128 x 1 28 pixels, which can be zoomed in or out optically to cover an area from 1 0 to 10000 cm2 (0.06 mm2 at 0.6 cm2 / pixel). The current technology provides an improved image field of 640 x 480 pixels. To guarantee the correct recognition and precise location of the anatomical characteristics studied, it is beneficial to simultaneously generate a reflex image of exactly the same body area (to accurately record the anatomical characteristics), and superimpose the reflection image on the emissive image to ensure accurate recording of any thermal abnormality found. This concept has been described in full in the publication of Dr. Michael Anbar, SPIE Proceedings 2020: 51 0-51 7, 1 993. DAT is useful in the diagnosis and management of a wide variety of disorders that affect neurological function or vascular. DAT is used to measure the periodicity of changes in blood perfusion over large regions of the skin, in order to identify a locally impaired neuronal control, thereby providing a quick and inexpensive screening test for skin cancer and for neoplastic lesions relatively shallow, such as breast cancer. The different clinical applications of DAT are described completely by Dr. Michael Anbar in 1994 in a monograph entitled "Quantitative and Dynamic Telethermometry in Medical Diagnosis and Management" (Quantitative and dynamic telethermometry in diagnosis and medical management), CRC Press I nc . , September 1994. The substantially lower cost of infrared equipment and the substantially lower personnel training requirements make DAT tests substantially less costly than radiological, ultrasonic or computer imaging tests based on nuclear magnetic resonance (N MR. ), such as CT (positron emission tomography) or M RI (magnetic resonance imaging). Being totally non-invasive, the DAT tests are risk-free and cause significantly less discomfort to the patient than some of the neuromotor tests, such as EMG, or nerve conduction tests. They also take significantly less time than other screening tests (CT, MRI or ultrasonic tests, respectively). 2. Measurements a. Thermo-regulation The skin, the largest organ of the human body, plays a major role in regulating the body's nuclear temperature. In its role of heat dissipation, the skin usually becomes hot when the body needs to dissipate excessive heat, and it becomes cold when the body must retain heat. Under moderate environmental conditions, the temperature of the skin depends mainly on the blood flow in the vasculature below the surface of the skin. In this way, in a way similar to other neurological or neuromuscular tests, substantial diagnostic information is involved in the dynamic behavior of the thermoregulatory system. The temperature of the skin reflects the physiological behavior of the cutaneous blood flow, which is modulated by the neurological control of relevant arteries and arterioles. Observing the temperature of the skin at any point on the skin as a function of time can provide direct information about the neurological control of the vasculature. Therefore, neurological disorders can be associated with the abnormal temporal behavior of skin temperature, in addition to changes in the spatial distribution of the thermoregulatory function, both of which are given for quantitative assessment. Although the temperature of the skin can vary over a wide range, depending on the environment and on the level of metabolic activity, it is regulated under normal conditions. This regulation may occasionally be less severe, such as during sleep, but even then some of the regulation of the skin is retained. Like any regulated parameter, including the core temperature, the skin temperature is expected to oscillate around a fixed point, even if the value of the fixed point does not remain constant. Even a system with a simple thermostat, such as a house heated or cooled by forced air, will show temperature oscillations from excesses of temperature and delays due to imperfect thermostats and different speeds of response and relaxation of the individual's heating and cooling processes. . In the human body, the maintenance of the temperature of the skin is due, in part, to the neuronal thermoregulation of vasoconstriction and vasodilation of the vasculature, thereby causing a characteristic modulation of the blood perfusion, unless the thermo- Neuronal regulation is inhibited or taken on a non-neuronal thermoregulatory control, such as nitric oxide (NO). In a complex regulated system, such as the human body, where there are several levels of nonlinear regulatory processes that interact with each other, many thermal regulatory oscillations are superimposed on one another. To untangle these systemic, regional and local thermal regulatory processes, one has to probe different parts of the body and different regions of organs. In order to maintain or change the temperature of the skin, the thermoregulatory neuronal system shrinks or dilates its blood vessels to change the blood flow velocity in the vessels. As indicated above, this is not the case if neuronal thermoregulation is inhibited in certain regions by an agent that functions independently, such as NO. This region is under non-neuronal thermo-regulatory control.

It has NOT been recognized as a ubiquitous vasodilator chemical messenger. Its main role seems to be the synchronization of intercellular and inter-organ functions, since it diffuses freely in the interstitial space. This has been discussed at length by Dr. Anbar in J. Pain Sympton Manage 14: 225-254, 1997. Therefore, it can inhibit sympathetic vasoconstrictor control in substantial regions of the microvasculature and can cause regional hyperperfusion. Subcutaneous and cutaneous hyperperfusion are manifested as hyperthermia of the skin above. The increased immune response, as found in local infections, autoimmune diseases and cancer, is associated with increased NO production. Under certain conditions, such as in breast cancer, the autocatalytic production of NO can occur, which results in oscillatory vasodilation, independent of and substantially different from the perfusion temperature oscillations caused by the neuronal thermoregulatory system. b. Mechanism of local hyperthermia of cancerous sinuses The breast hyperthermia associated with cancer is caused by impaired neuronal thermoregulation. This impaired neuronal control is caused by the excessive production of NO by breast cancer cells and by macrophages that react with the neoplastic tissue. This activity is an expression of the immune response, but NO generated by macrophages is a major factor for the death of microorganisms or mammalian cells recognized as foreign. This mechanism is described in full in a publication by Dr. Michael Anbar, Cancer Letters 84 (1): 23-29, 1 994. The generation of NO by cancer cells increases the blood supply and intensifies the probability of metastasis. The NO generated by the breast cancer cell and the macrophage, which diffuses freely throughout the surrounding tissues, interacts with the vasoconstrictor receptors in the arterioles, in order to vasodilate the vasculature. This results in the intensified perfusion of the capillary bed. As a consequence of the synergistic multiphasic action characteristic of NO, this increased perfusion intensifies the growth of breast cancer cells. The rate of NO production is further enhanced by the presence of ferritin, the level of which is significantly elevated in cancerous breast tissue. Fe2 + released from ferritin is used to produce more NO synthase (NOS), an iron carrier enzyme that produces NO from arginine, and thus results in a further increase in the rate of NO production. Additionally, it has been shown that NO releases Fe2 + from ferritin, by forming a NO-ferritin complex. This results in an autocatalytic production of NO. Fe2 + reacts with nitrite, the NO oxidation product, to reform NO, and also eliminates superoxide radicals (HO2), which are usually the main NO purifiers. This maintains the high local level of NO and the hypoperfusion of the capillary bed. The ferritin-dependent intensification of NO production appears to be specific for neoplastic cells and is less likely to occur with other inflammatory situations, including those induced by microorganisms.

It is not easily disseminated interstitially; therefore, the volume of the capillary bed that is hyperperfused is many times greater than that of the tumor and its immediate surroundings. This explains the extensive regional hyperthermia associated with tiny antigenic tumors. The rate of production of NO in the cancerous sinus is also amplified by the positive effect of local temperature on the production of NO by the cancer cell and by macrophages. All these autocatalytic effects obscure the negative feedback of the NO level in the speed of enzymatic production of NO. Like any autocatalytic process, the NO production rate is expected to oscillate. It is expected that the rate of NO production will rise exponentially due to positive Fe2 + feedback and temperature, and then fall when certain precursors, such as arginine or oxygen, are locally suppressed temporarily. Similar positive feedback, resulting in vascular oscillations, has been demonstrated for NO under ischemic conditions in the brain, where lack of oxygen results in reduced NO production and subsequent vasoconstriction, which further limits the oxygen supply. NO generated by cancer cells and by macrophages diffuses along the capillary bed and inhibits, or even takes complete control of the modulation of blood perfusion from the neuronal system, and therefore, obscures temperature swings -neuronal regulators. Due to the degree of perfusion and the surface temperature of the upper skin follow the same oscillatory behavior, the temporal behavior of skin temperature over the region of cancer cells does not follow the normal neuronal thermoregulatory modulation in blood perfusion. Therefore, the region does not maintain the normal temperature oscillations or thermoregulatory frequencies that result from them. The frequencies of temperature oscillations observed on the cancerous sinus differ substantially from those observed on the noncancerous sinus (normal). The oscillations on a normal sine are caused by the neuronal thermoregulatory processes, which follow several characteristic frequency bands. On the other hand, the cancerous area of the breast, which loses its thermo-regulating neuronal control due to the over-production of NO, is characterized by the disappearance of neuronal oscillations and the appearance of oscillations due to the autocatalysis of the production of NO, with its normal frequency bands. Due to the latest autocatalytic processes, which are controlled by the temporary local suppression of one of the NO precursors, they are totally different in nature from the neurological feedback processes manifested in the neuronal frequency bands, there is no possibility of overlapping frequency of these completely different processes over all frequency bands. The disappearance of neuronal frequencies over substantial parts of the cancerous sinus is enough to identify pathology. Additionally, the appearance of the autocatal frequencies characteristic of overproduction of NO is, by itself, sufficient to identify the pathology. The substitution of one set of frequency bands for the other is a criterion of even more strict pathology. Under conditions of overproduction of extravascular NO and its consequent hyperperfusion, HST reaches a maximum value that oscillates at a frequency that depends on the modulated autocatalytic velocity of NO production. Therefore, the frequency bands of HST modulation can be used as a criterion independent of the pathology. The combination of the temperature and HST criteria increases the sensitivity and specificity of the DAT test. Because, unlike classic breast thermography, the DAT test does not use absolute temperature or temperature differences as a diagnostic parameter, there is less need to allow patients to reach thermal equilibrium with the environment. This means a faster change of patients, and hence lower cost per test. Moreover, the environment does not have to be strictly controlled, as long as it does not contain modulated infrared emissions in the frequency ranges of interest, which could be reflected from the skin. This decreases the cost of the installation. Because the overwhelming majority of classified subjects are free of malignancy, the administration of the test can be completely computerized and does not require a medical expert. Extensive computerization, which allows the use of semi-skilled, easily trained personnel, provides a substantially lower cost of this classification test, as compared to the prior art (including classical thermological tests). c. Alternative methods to measure periodic changes in perfusion As stated, DAT is the method of choice to measure the modulation in blood perfusion. The thermometry of micronodes of tissue volume and skin thermometry using arrays of thermal resistances, and two alternative methods for dynamically measuring temperature. However, microwave thermometry has a significantly lower spatial resolution (by a factor of 10,000) and lower sensitivity (by a factor of 1 0 to 1 00) and may require direct contact of the electrodes (antennas) with the breast. which requires skill and additional time. Area thermometry by electrical resistances with adequate spatial resolution, requires the assembly of many hundreds or even thousands of electrical resistances across the entire surface of the sinuses, which is a prohibitively embarrassing process. Liquid crystal contact thermography (LCCT) provides inadequate low accuracy (> 0.5 ° C) and response times that are too long to be useful in quantitative dynamic measurements. Other methods to continuously measure perfusion modulation of the capillary bed in the breast include ultrasound (measuring changes in ultrasonic impedance, because the sound velocity is temperature dependent and due to changes in the average tissue density (hyperperfusion), or by measuring changes in the average velocity of red blood cells by Doppler change, however, ultrasonic perfusion measurement can not be done simultaneously in all areas of one or both breasts, it also requires a highly trained expert to measure changes In addition, it is necessary to apply a coupling lotion in order to make contact with the ultrasonic probe and the sinus.The application of such coupling lotion and the contact of the ultrasonic probe can alter the perfusion by affecting the tactile and thermal neuronal sensors Another method to measure the modulation in perfusion sa nguinea is the Doppler infrared velocimetry (I RDV), which measures the Doppler change of the near infrared radiation (approximately 1 μm) reflected from the erythrocytes. However, I RDV can not monitor the modulation of blood perfusion over large areas in a reasonable time (it would take hours to accumulate the same information about the temporal behavior of blood perfusion that can be measured in approximately 30 seconds by DAT). Another method to measure the modulation in blood perfusion emission is a simple photon emission computed tomography (SPECT), which measures the local concentration of radioactively labeled compounds in tissues within the human body. Red blood cells can be labeled by a radioactive isotope and their concentration in a tissue of interest is a measure of perfusion. However, SPECT does not measure concentrations with an accuracy that provides monitoring of small perfusion modulations, ie approximately 1%. Moreover, SPECT carries radiobiological risk to the patient, is more uncomfortable and slow, and involves much more expensive instrumentation compared with DAT.

Another method for measuring modulation in blood perfusion is impedance plethysmography (because the ionic conductivity depends on the amount of plasma between the electrodes). This method, which requires the assembly of an array of electrodes in both breasts by an expert technician before any measurement can be made (which makes it substantially more expensive), is also less sensitive for minute oscillations; In addition, its spatial resolution (limited by the number of electrodes used) is significantly lower than that achieved by DAT. Yet another method to continuously measure perfusion modulation of the capillary bed in the breast is MRI. MRI can be used to dynamically monitor blood perfusion and detect characteristic oscillations associated with the controlled mechanism of autocatalis. Nevertheless, MRI requires instrumentation much more expensive than DAT (by a factor of 30 to 60), and an examination would be much more uncomfortable and slow. Most importantly, MRI can be used to identify deeply located cancerous lesions, ones that do not affect cutaneous or subcutaneous perfusion, and therefore, are not receptive to DAT tests. Because the modulation of the blood perfusion of the cancerous sinus is directly related to the modulation of NO in the affected tissue, measuring the concentration of NO and its modulation could be used as an alternative diagnostic method for the detection of cancer. The most preferred method for measuring NO concentration in human tissues is by paramagnetic electron resonance (EPR) operating in an imaging mode. The EPR imaging is conceptually very similar to MRI, however, it uses different electromagnetic frequencies. The cost of an EPR imaging test will be comparable, as a result, with an MRI test. As with MRI, EPR imaging can also be used to identify deeply located cancerous lesions that do not affect cutaneous or subcutaneous perfusion and therefore, are not receptive to DAT tests.

BRIEF DESCRIPTION OF THE DRAWINGS The invention will become more readily apparent from the following description of the preferred embodiments thereof shown in the accompanying drawings, wherein: FIG. 1 is a schematic representation of neuronal modulation of perfusion in a healthy breast. FIG. 2 was a schematic representation of the modulation of perfusion in a cancerous sinus and showing each of the steps of detecting cancerous lesions according to the present invention.

DETAILED DESCRIPTION OF PREFERRED MODALITIES As shown in Fig. 1, a non-cancerous region of breast 1 0 maintains a required temperature by neuronal modulation of blood perfusion 1 2. In addition, this modulation of blood perfusion generates temperature oscillations 14, from which an infrared flow 1 8 corresponding to the temperature of the skin 16 is detectable. As shown in FIG. 2, a cancerous region 20 of breast 10 contains cells that produce NO 22 and also elicits an immune response 24, which enhances the activity of macrophages 26 that also produce NO 22. This production of NO is intensified by the elevated level of ferritin. in cancerous breast tissue. Moreover, the presence of NO vasodilates the vasculature 30, causing enhanced perfusion of the capillary bed 32. The presence of NO also impairs the neuronal control 34 of vasoconstriction and vasodilation of the vasculature, thereby changing the modulation of the perfusion of the vasculature. capillary bed 32 and temperature oscillations 36 manifested therefrom. The abnormal modulation of the perfusion provides an abnormal infrared flow 40. According to the present invention, an infrared camera 42 is positioned to provide infrared images of the human body, for example, sinus 1 0. A preferred camera is equipped with a photodetector infrared quantum cavity (QWI P) of GaAs focal plane array 640 x 480 (FPA). Such a chamber can record the modulation of skin temperature and its homogeneity with a precision greater than ± 2 milligrams C, that is, less than 1/20 of physiological modulation of temperature and homogeneity of human skin. The infrared images are transmitted to a CPU 44, which processes the recorded infrared flow information to determine if the sinus is normal or cancerous. In the first case, the modulation of perfusion changes of the spatial homogeneity of the skin temperature are dictated by neuronal thermoregulatory frequencies 46 (Fig. 1). In a cancerous breast, the spatial homogeneity of skin temperature is dictated by non-neuronal thermoregulatory frequencies 48 (Fig. 2). This data is the output information on a CRT 50 monitor. The printed presentations of the output information of the CPU 52 of the infrared data collected in a usable ready format, as will be explained in detail herein. Thus, the classification technique of the present invention uses the characteristic changes in the temporal behavior of the blood perfusion caused by the production of intensified NO by cancer cells and macrophages 26 and is amplified by ferritin 28 to detect an immune response. induced by neoplastic disease. The oscillation of the temperature of the blood perfusion associated with the autocatalytic production of NO, as well as the decrease or disappearance of the neuronal TRFs are used as the diagnostic parameters. Like the temperature of the skin, HST changes from neuronal modulation to NO controlled. The HST TRFs are, therefore, additional independent diagnostic parameters. Neuronal and autocatalytic oscillations are measured by fast Fourier transform (FFT) analysis, a method of analysis well known in the art, of the temporal behavior of sinus perfusion (manifested in the temporal behavior of sinus temperature and of HST). As discussed before, the modulation of the perfusion of the capillary bed in the breast can be measured continuously by several techniques. Due to its sensitivity, rapid response time, data acquisition speed and low cost, DAT is the preferred method for measuring capillary bed perfusion modulation and identifying aberrations in parts of human tissue. It has a sensitivity of up to 0.001 ° C (ie, approximately 50 times smaller than the level of temperature modulation under conditions of normal perfusion; the ictical autocatal process is expected to have an even higher level of modulation) and a response time of < 10 msec The HST TRFs are derived from the same DAT data, using the same computational technique, only in this case, the measured parameter used in the calculation is the "micro" spatial variation of the temperature. As described in depth in the serial US application no. 08/368, 161, which is authorized for the agent of the present invention and is incorporated herein by reference, DAT facilitates simultaneous monitoring of the entire areas of both breasts, including their side views when using mirrors. Such simultaneous monitoring over time of whole areas of both breasts is the preferred method. It allows the accumulation of hundreds of sequential thermal images that are then subjected to FFT to extract the frequencies and amplitudes of periodic changes in each pixel of the image. To measure the HST, the image is subdivided into a matrix of small areas, each corresponding to 64 mm2 of the skin, and the temperature values of the pixels in each subarea of the image are averaged. The variation of the average temperature is used to calculate the HST of each subarea. The HST values of all the accumulated images are then analyzed by FFT to extract the corresponding frequencies from the standard deviation of average temperature requires a computerized, highly stable, high resolution, highly sensitive infrared camera, which preferably operates in the range of 8 to 14 μm. To meet the specific needs of DAT, it is preferred that the camera computer be programmed to quantitatively analyze the temporal behavior of many thermal images with sufficient resolution, for example, 640 x 480 pixels. Using a state of the art 640 x 480, the geometry of a 300 x 600 pixel image of both sines can be analyzed. Although successful results can be achieved by analyzing the temporal behavior of at least 1 28 thermal images, it is more preferred to measure 1024 thermal images. These images can be stored temporarily to perform the FFT in the time series of temperature values of each pixel or subarea. The FFT produces the frequency spectra of each pixel along with the relative amplitude of each TRF. The computer program then tabulates or displays the spatial distribution of the TRFs within a given range of relative amplitudes on the image. The same procedure is followed with the HST data. When TRFs are displayed with amplitudes above a given threshold (for example, above 5% of the total thermal modulation, or a certain cut-off value in the order of range of amplitudes), a subset of characteristic neuronal frequencies is identified. on breast-free areas of immune response enhanced by cancer; these TRFs are significantly attenuated or completely absent in areas that rest on sinuses with neoplastic lesions. The last areas are characterized by substantially different TRFs caused by the autocatalytic production of NO and exhibit, therefore, non-neuronal thermo-regulating behavior. In addition, the latter areas are characterized, consequently, by abnormal modulation of blood perfusion and abnormal temperature fluctuations. A hard copy image is then generated to allow an expert to anatomically identify the location of the abnormal area or areas. The infrared camera can also be equipped with video CCD to produce a reflective (visual) image of the patient's breasts. The reflexive image allows an accurate anatomical location of areas with abnormal temporal behavior, information necessary for further examination of such a patient. The computer algorithms that facilitate this calculation are as follows: A. Use of temperature values of individual pixels and calculation of TRFS. 1 . The computerized camera takes a picture of the infrared flow (300 x 600 pixels) and converts it into a thermal image, where each pixel has a certain temperature value. This process is repeated, preferably, thirty times in a second until 1024 thermal images have been accumulated and stored. 2. The areas of interest in the image are subdivided into sub-areas of 36 to 64 pixels, each corresponding to four square millimeters of the skin, depending on the resolution of the camera. The average temperature and standard deviation of each of the sub-areas in each of the 1024 images are then calculated. These average temperature values constitute a simple series of times that is then subjected to FFT analysis to extract the contributing frequencies and their relative amplitudes. The computer stores the FFT spectrum for the given group of pixels. The computer repeats the same procedure for each of the selected groups of pixels in the image. 3. The computer selects the FFT spectra of the selected points and displays colored bitmaps of the relative amplitudes in any displayed range of frequencies to identify clusters of points with abnormal frequencies. 4. If procedure # 3 does not definitively identify the abnormal groupings, the computer prints a message that the findings are negative and the patient is normal. Otherwise, the computer proceeds with procedure # 5. 5. The computer examines all the pixels in the abnormal areas identified in procedure # 3 by the 1 0 most prominent frequencies to identify the frequencies that are characteristic of cancer. 6. If procedure # 3 identifies a definitely abnormal area, even if procedure # 5 becomes negative, the computer prints a color image of the breasts. If procedure # 5 produces a confirmation, the computer prints another color image with the abnormal areas.

B. Use of the HST values and the TRST calculation of HST. 1 . The computer subdivides the image into 2048 square sub-areas of 64 pixels each (corresponding to approximately 64 mm2 of the skin), and calculates the average temperature value (AVT) and standard deviation (SD) of each subarea. The SD values can be treated identically to the AVT values of pixel groups according to procedures # A1 to A6. 2. The computer then calculates the HST value for each sub-area: HST = AVT / SD. The time series of HST values are then analyzed by FFT to produce HST TRFs, following procedure # A2. Alternatively, the SD time series can be treated in the same way. 3. The following calculation steps follow procedures identical to # A3 to A6, except that the absolute amplitude are in dimensionless units of HST. 4. Following the last procedural step # A6 with the finding of HST TRFs, if it is positive, it can be used to confirm the findings of the temperature TRFs. In this case, there are four independent diagnostic parameters and the printing of the findings must be done with a four-color printer. 5. The output information of the visual image can be done in half tone monochrome on a transparent mat that can be superimposed on the abnormal area image, to accurately identify the anatomical position of the abnormal area.

The difference between normal and cancerous sinuses is accentuated by a thermal challenge (cooling) of the sinuses, which only affects the thermo-regulatory neuronal system and, consequently, affects only the TRFs in areas that are not vasodilated by extravascular NO production. excessive The computer is programmed to search the frequency bands of the neural and NO controlled TRFs in each statistical subset of pixel squares (for example 36 or 64 pixels) of the image processed with FFT. If the computer does not find any statistical subset with neuronal TRFs having exceptionally low or zero amplitude (except at the periphery of the image that does not show the skin), and there are no pixels or subareas that have autocatalytic TRFs colled by NO with a significant amplitude, the findings of the test are declared as negative (ie, normal). This finding is then confirmed when calculating and analyzing the TRFS of HST. If the computer finds certain pixels with exceptionally low neuronal TRFs and if those pixels exhibit autocatalytic TRFs colled by NO, the test findings, preferably the findings of the DAT test, will be classified as pathological. This finding is then confirmed by analyzing the HST data, as described by the uncooled breast. The cooling of the sinuses (by a soft flow of forced air) reaches the maximum sensitivity and specificity. Such additional tests are administered as a confirmatory test only for patients who show a positive test result without cooling.

Although the invention has been described in detail for purposes of illustration, it will be understood that such detail is solely for that purpose and that variations may be made thereto by those skilled in the art without departing from the spirit and scope of the invention, except as may be be limited by the claims.

Claims (9)

1. REVIVALATION IS 1 . A method for detecting breast cancer tissue in humans, comprising the steps of: a) providing a means to detect periodic changes in spatial temperature homogeneity in areas of a human breast; and b) detect, with the detection means, periodic changes in the spatial homogeneity of temperature in areas of the human sinus.
2. 2. The method of claim 1, wherein the detection means includes DAT.
3. 3. The method of claim 1, wherein the detection means includes a system of infrared perception and imaging.
4. A method for detecting cancerous tissue in humans, comprising the steps of: a) providing a means for measuring the infrared flow, periodically and simultaneously, emitted from a plurality of areas of human skin; b) measuring, periodically and simultaneously, the infrared flow emitted from the plurality of areas of human skin; c) providing a means for detecting periodic oscillations in infrared flow emitted from the plurality of human skin areas; and d) detecting changes in periodic oscillations in infrared flow emitted from the plurality of areas of human skin.
5. 5. The method of claim 4, wherein the detection means is DAT.
6. 6. The method of claim 4, wherein the detection means includes a system of infrared perception and imaging.
7. 7. A method for detecting breast cancer, comprising the steps of: a) providing a means to detect periodic changes in spatial temperature homogeneity in areas of a human breast; and b) detecting, with the detection means, periodic changes in the spatial temperature homogeneity in areas of said human sine.
8. 8. The method of claim 7, wherein the detection means is DAT.
9. 9. The method of claim 7, wherein the detection means includes a system of infrared perception and imaging. The method of claim 7, comprising the additional steps of: a) providing a means for cooling the human breast; and b) cooling, with the cooling medium, the human breast to accentuate the variations between cancerous and non-cancerous areas of the human breast.