Patent Document

CROSS REFERENCE TO RELATED APPLICATIONS 
       [0001]    This patent application claims priority to Provisional Patent Application, 61/238,949, filed Sep. 1, 2009. 
     
    
     INCORPORATION BY REFERENCE 
       [0002]    All publications and patent applications mentioned in this specification are herein incorporated by reference in their entirety to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. 
       REFERENCES 
       [0000]    
       
         [1] Ruigang Liu, Xiuzhen Dong, Feng Fu, Fusheng You, Xuetao Shi, Zhenyu Ji, Kan Wang,  Multi - frequency parameter mapping of electrical impedance scanning using two kinds of circuit model . Physiological Measurement: July 2007 Volume: 28 Start Page: S85. 
         [2] Tyna A Hope 1 and Siân E Iles2 , The use of electrical impedance scanning in the detection of breast cancer . Breast Cancer Res. 2004; 6(2): 69-74. 
         [3] J. Jossinet and B. Lavandier,  The discrimination of excised cancerous breast tissue samples using impedance spectroscopy , Bioelectrochemistry and Bioenergetics, Volume 45, Issue 2, May 1998, Pages 161-167 
         [4] Arum Han, Lily Yang and A. Bruno Frazier,  Quantification of the Heterogeneity in Breast Cancer Cell Lines Using Whole - Cell Impedance Spectroscopy , Clinical Cancer Research 13, 139, Jan. 1, 2007. doi: 10.1158/1078-0432. CCR-06-1346 
         [5] Alexander Stojadinovic, Aviram Nissan, Zahava Gallimidi, Sarah Lenington, Wende Logan, Margarita Zuley, Arieh Yeshaya, Mordechai Shimonov, Moshe Melloul, Scott Fields, Tanir Allweis, Ron Ginor, David Gur, and Craig D. Shriver,  Electrical Impedance Scanning for the Early Detection of Breast Cancer in Young Women: Preliminary Results of a Multicenter Prospective Clinical Trial , Journal of Clinical Oncology, Volume 23, Number 12, Apr. 20, 2005: 2703-2715 
         [6] WANG Kan, WANG Ting, FU Feng, JI Zhen-yu, LIU Rui-gang, LIAO Qi-mei and DONG Xiu-zhen,  Electrical impedance scanning in breast tumor imaging: correlation with the growth pattern of lesion , Chinese Medial Journal 2009; 122(13):1501-1506 
         [7] T. Morimotoa, Y. Kinouchib, T. Iritanic, S. Kimuraa, Y. Konishia, N. Mitsuyamaa, K. Komakia, Y Mondena,  Measurement of the Electrical Bio - Impedance of Breast Tumors , European Surgical Research Vol. 22, No 2, 1990; 22:86-92 (DOI: 10.1159/000129087). 
         [8] Alexander Stojadinovic, M.D., Aviram Nissan, M.D., Craig D. Shriver, M.D., Sarah Lenington, Ph.D., David Gur, Sc.D,  Electrical Impedance Scanning for Breast Cancer Risk Stratification in Young Women , Hermann Scharfetter, Robert Merva (Eds.): ICEBI 2007, IFMBE Proceedings 17, pp. 675-678, 2007. 
       
     
       FIELD OF THE INVENTION 
       [0011]    The application of a signal to tissue and differentiating tissue characteristics such as the presence of benign or malignant growths from normal tissue based on impedance characteristics. 
       BACKGROUND OF THE INVENTION 
       [0012]    Bio-impedance of breast tumors has been a source for numerous scientific research studies since discovery of electricity by Volta in 1800. It was the Cole brothers (in 1930) who mathematically and physically described dielectric properties. Cole-Cole equations are used in bio-impedance analysis. Since the late 1960&#39;s, bio-impedance analysis has benefited from the advent of microprocessors and digital signal processing. 
         [0013]    The method can also be used to characterize biological tissue electrical properties in many different applications including blood analysis, body muscle and fat content as well as in estimating the length of the root canal in teeth see U.S. Pat. No. 6,425,875 “Method and device for detection of tooth root apex.” 
         [0014]    Electrical Impedance Scanning (EIS) has been described in literature [1] [2] and machines have been built to be used on patients. The EIS of the breast relies on body transmission of alternating electricity using an electrical patch attached to the arm and a hand-held cylinder. The electrical signal flows through the breast where it is then measured at skin level by a probe placed on the breast. Examples of such devices are the T Scan 2000 from Mirabel Medical Systems, which has been cleared by the FDA for adjunctive diagnosis in conjunction with mammography, and the follow-on T Scan 2000 ED. Mirabel devices are covered under multiple patents among which are Andrew L. Pearlman (U.S. Pat. No. 7,141,019), Ron Ginor (U.S. Pat. No. 7,302,292) and Ginor and Nachaliel (U.S. Patent Application Pub. No. 2007/0293783). Other devices are the one from Biofield Corp. (Cuzick et al, U.S. Pat. No. 6,351,666), and the device of Richard J. Davies (U.S. Pat. Nos. 6,922,586 and 7,630,759). 
         [0015]    The benefits of having a non-mammographic mechanism to screen for patients whose age is less that age 50 are significant. Below age of 40, radiation from use of screening mammography will cause more cancer than it saves. Between 40 and 50 there is a break even where one saves approximately as many of cancers caused. Above 50 years of age mammography works well because a tumor contrasts well against normal breast tissue. Below age 40 the density of the breast tissue is so high that it difficult to impossible to differentiate from a tumor. The same is not quite as true for women in the age group of 40 to 50 but the problem with mammographic differentiation between normal breast tissue and cancer remains. 
         [0016]    Asymptomatic young women under the age of 40 are not routinely screened (in the United States) but instead depending on breast self examination (BSE) and clinical breast examination (CBE). Carcinoma of the breast is generally more aggressive in younger women. The availability of a diagnostic test that does not involve radiation would be of significant benefit. 
         [0017]    Mammograms only demonstrate presence of calcium and not all DCIS masses have calcium deposits. MRI and PET only detect increases in vascularity which may or may not be present. One consideration in mammography is that the results are not necessarily stable; some 30% of “cancer” detected on mammography disappears. 
         [0018]    Another factor is the detection of breast cancer and other abnormalities is the cost of doing procedures. It would of significant benefit, particularly in developing countries, to have a low cost procedure. Of course, lower cost and resulting wider availability is important in developed nations as well. 
       SUMMARY OF THE INVENTION 
       [0019]    Breasts can be examined using an electrical impedance scanning method, which has been previously described in many publications [1] [2] [3]. In this novel invention, the method is improved to quickly scan through multiple frequencies by using a complex waveform containing even and odd harmonics across several decades of frequencies. 
         [0020]    Uses are:
       1. Detection of Ductal Carcinoma In Situ (DCIS) other malignant tumor masses, or benign breast masses   2. Follow up of changes in masses over time   3. Assess effectiveness of treatment to eradicate DCIS or other tumors.       
 
         [0024]    The invention provides significant benefits, first by avoiding use of radiation which can generate the cancers that mammography that the test is meant to detect and perhaps other cancers and second by offering a low-cost diagnostic test and tracking vehicle. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0025]      FIG. 1  shows a block diagram of the impedance application system. 
           [0026]      FIG. 2  illustrates the source waveform with all even and odd harmonics. 
           [0027]      FIG. 3  shows the phase of the source waveform. 
           [0028]      FIG. 4  illustrates the magnitude response of regular breast tissue. 
           [0029]      FIG. 5  shows the phase response of a regular breast tissue. 
           [0030]      FIG. 6  illustrates the magnitude response of tumor tissue. 
           [0031]      FIG. 7  shows the phase response of a regular and tumor tissue. 
           [0032]      FIG. 8  shows saw tooth waveform. 
           [0033]      FIG. 9  shows the FFT magnitude of the saw tooth waveform. 
           [0034]      FIG. 10  shows the FFT phase of the saw tooth waveform. 
           [0035]      FIG. 11  illustrates the breast cancer test configuration. 
       
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0036]    The amplitude and phase of several harmonics within a range of frequencies creates a signature of the breast growths allowing differentiation of benign and malignant masses. Our invention is novel in that it differentiates normal from abnormal tissue based on observing secondary effects of changes in dielectric properties due to increased numbers of cells based on phase and amplitude of multiple levels of harmonics without the necessity to measure absolute capacitance and resistance values. The invention allows differentiation of benign masses (e.g., tumor or infections) versus malignant masses versus other cellular changes. Our approach is not impacted by patient to patient differences. 
         [0037]    Other impedance-related approaches (e.g., those referenced above from Mirabel Medical Systems, Biofield, and Davies) depend on measuring absolute capacitive and absolute resistive properties to compute the Cole-Cole function shape. Measuring absolute values is difficult and inherently error prone, especially since they will vary from patient to patient. 
         [0038]    An embodiment of a suitable device is shown in the Block Diagram of  FIG. 1 , which illustrates the block diagram of the invention for breast-mass detection. After the unit powers up through the use of user interface  100 , the microprocessor  110  will load the characteristics of the desired square wave to the generator  120 . If another wave type were used (e.g., sine or saw tooth), generator  120  would generate that wave type. As commanded by the medical professional through the input interface  100 , the microprocessor  110  will start coherent sampling by synchronizing the waveform generation  120  and waveform capture  150 . Output stage  130  assures proper voltage levels and their rising and falling edges. The output stage  130  also distributes the signal to multiple electrodes as shown in  FIG. 11 . Microprocessor  110  controls the main frequency and triggers the current capture  150 . The biological tissue  140  is the breast under examination. The sampled current  150  is digitized by Analog to Digital Converter (ADC)  160 . A Fast Fourier Transform (FFT) is computed by microprocessor  110  on 2̂n samples received from ADC  160 . For practical considerations, the n should be equal or greater than 8. Typically it would be 12, but with microprocessor advances this can be increased for better accuracy. The resulting FFT data with its magnitude and phase are compared by the microprocessor  110  with the identifying references stored in it. The references may include markers identifying benign or malignant tumors including their relative position to a probes being tested. All the conclusions of testing by the microprocessor  110  are sent to the display  100  to inform the medical professional. The circuit requires coherent source and sampling conditions to achieve the spectral resolution needed to precisely identify changes in amplitudes and phases caused by masses, including growing cancer cells. Coherent sampling is superior over any type of data windowing or interpolation. A wide spectral band is used from around 20 kHz to several MHz with odd harmonics. The non-linearities in the tissue will contribute to generation of even harmonics at much smaller amplitude. Our invention can be used in the ranges of 10 kHz to 1 MHz, or from 1 MHz to approximately 100 MHz, and from 100 MHz to 10 GHz. 
         [0039]    In one embodiment, the square wave main frequency  200  in  FIG. 2  is set to 10.74219 kHz. This satisfies the coherency condition of 11 cycles, 4096 samples and 250 ns sampling. It places the 93 rd  210 harmonic at 999.0234 kHz. This setting takes into computation 48 harmonics. Research papers have indicated 100 kHz to 1 MHz to be affected by growing tumor cells [4] [5]. The square wave rising and falling edges were set to 250 ns giving odd harmonic content. 
         [0040]    All harmonics in the band of the source square wave, as shown with their magnitude in  FIG. 2  and the phase in  FIG. 3 , are used in the computation. The results of magnitude and phase changes  300  in  FIG. 3  are compared with the set of the reference amplitudes and phases as they identify cancer cells [2] [6] [7] [8]. Alternatively, a set of reference amplitudes and phases as they identify masses of benign cells can be used. 
         [0041]      FIG. 4  shows an example of breast-tissue current with its magnitude response to the square-wave stimulus and  FIG. 5  with its phase response. The model of a tumor tissue includes a non-linear capacitor. The harmonic level  400  in  FIG. 4  is shifted to larger value. The phase plot  500  in  FIG. 5  has changed shape.  FIGS. 6 and 7  respectively show examples of breast-tissue current in magnitude  600  in  FIG. 6  and phase responses to the square-wave stimulus for malignant breast tissue.  FIG. 7  compares healthy tissue response with tumor tissue response  700 . 
         [0042]    The phase and amplitude changes across multiple frequencies differentiate the tissue into healthy cells, benign mass, and malignant tumor. The amount of phase shift at particular frequencies creates a marker to be identified during clinical studies. Having in excess of 40 harmonics, the cell signature makes the differentiation very visible. 
         [0043]    Some of the scientific publications show analysis of dielectric properties of tumor cell in the frequency range up to 10 GHz. A modified saw tooth waveform  800  in  FIG. 8  with coherent ratio between its period  810  and sampling interval would cover this range. The plateau  820  in the saw tooth could be made variable to tune in into the response of specific tumor cells. 
         [0044]    The magnitude of Fast Fourier Transform is shown on  FIG. 9 . The waveform shows both even and odd harmonics  900 . The phase response of the saw tooth waveform shown in  FIG. 10  exhibits small variations in the bandwidth of interest  1000 . 
         [0045]    The waveform sources are distributed around the breast  1100  in a constant angular angle as shown in  FIG. 11 . The nipple is used to connect the detector  1110 . The connection can be made via a cap or other surface connection or via an inserted probe. Generating waveforms and collecting data is done by stand-alone device  1120 . The resulting data is transferred to a computer  1130  for visual and mathematical analysis. The receiving electrode in  FIG. 11  may be one covering the nipple, or for increased localization capability may be an electrode made of insulated wire with a bare conducting tip inserted into one of the (typically on the order of nine). For differentiated signatures, this approaches permits greater localization. In another embodiment the source and receiving electrodes are incorporated in a brasserie. 
         [0046]    The ECG/EKG pads are distributed in the area where breast attaches to the chest wall. The ECG/EKG pads can be replaced with 30 gauge needles to achieve a higher degree of accuracy. 
         [0047]    The system is not limited to the use of a square wave. A sine wave can be used with the same coherent setting for multiple frequencies covering similar or the same harmonics. There could be one sine wave source with a non-linear gain element creating harmonics without need to step the frequencies. 
         [0048]    Analyzing magnitude and phase for over 40 harmonics in frequency span from 10 kHz to 1 MHz will be a substantial source for the signature differentiating dielectric properties of healthy tissues versus tumor tissue. Many publications show Cole-Cole charts with significant changes when tumor cell start to grow in this frequency span. 
         [0049]    In other embodiments, the number of source electrodes is varied. The larger the number of source electrodes, the higher the resolution of localization. For example having eight source electrodes arranged around the perimeter of the breast will double the localization capability since the area of the breast will be divided into eight regions as opposed to quadrants. Where in some applications of the device, one only wants to do screening to know whether a lesion is likely present or not, in others being able to localize would be important. This may occur, for example, if one is tracking changes in the lesion. 
         [0050]    Feedback to the user as to results may take multiple forms. In one embodiment, the presence an abnormality is a non-visual feedback. This is supplied by an auditory or vibratory cue. Tone patterns can provide either a binary or relative magnitude, including level of probability. In another embodiment, the presence of an abnormality is indicated by a simple visual cue such as an LED display, either binary or relative magnitude, including level of probability. 
         [0051]    In another embodiment, the presence of an abnormality is indicated by an intermediate visual display presenting text or graphical results, including level of probability. In still another embodiment, the presence of an abnormality is indicate by a complex visual display presenting raw data and processed graphical information, including level of probability. 
         [0052]    The invention can be used as a screening device for initial, non-radiation involving, low-cost exam where, if the result is positive, a higher functionality version of the invention is used (for example, one with full display capabilities) and/or other techniques such as mammography, Magnetic Resonance Imaging, Positron Emission Tomography, and ultrasound. For screening purposes it is usually important to adjust the detection level so that the results are biased to having false positives and avoiding false negatives since the false positive tests can be followed up more intensively, or, in some cases, by repetition of the initial type of test. One can adjust relationships among true positives and negatives and false positives and negatives. Specificity and sensitivity can be adjusted as well. 
         [0053]    An important approach to the testing of such devices is the ability of comparing the healthy tissue in one breast to a potential lesion in the other breast in the same patient. 
         [0054]    While the approach described is applied to breast tissue, the same techniques with the same parameters can be applied for detecting abnormalities in other tissues, including, but not limited to, for example, lung and prostate tissue, using suitable source and receiving electrodes. 
         [0055]    It is noted that any embodiment described herein for exemplary purposes is, of course, subject to variations. Because variations and different embodiments may be made within the scope of the inventive concept(s) herein taught, it is to be understood that the details herein are to be interpreted as illustrative and not in a limiting sense.

Technology Category: 1