QG,QWHUQDWLRQDO&RQIHUHQFHRQ(OHFWURQLF'HVLJQ,&('$XJXVW3HQDQJ0DOD\VLD Potential of Urine Dielectric Properties in Classification of Stages of Breast Carcinomas Ausilah Al-Fraihat1,a A. Wesam Al-Mufti2, a, U. Hashim3, b, and Tijjani Adam2,c The Hashemite University P.O. Box 150459, Zarqa 13115, Jordan [email protected] Nano structure lab on chip research group Institute Nano Electronic Engineering, Universiti Malaysia Perlis. (UniMAP), 01000 Kangar, Perlis Malaysia a [email protected], b [email protected] Abstract--Some evidences have been found that urine can be used as a biomarker for the detection of many types of diseases. The purpose of this study is to use permittivity of urine to assess whether different stages of breast cancer are significantly different. Changes in electrical resistance of urine samples to applied microwaves were measured over a frequency range between 10MHz to 20GHz. This is carried out by the measurement of samples’ response to applied microwave energy using network vector analyzer. SPSS was used to find out the significant difference in urine permittivity values across different stages of breast cancer. The results show significant difference between stage 1 and stage 2 in all dielectric parameters of urine permittivity. Significant difference was also found between stage 2 and stage 3 in both dielectric constant and loss factor parameters while the significant difference between stage 1 and stage 3 only exists in loss factor parameter. The results suggest that it is possible to estimate the stage of breast cancer based on the dielectric properties of urine. Interest and research in studying the electrical properties of breast tumors began several decades ago. All of these studies are based on the consensus that electrical properties of breast tumors are different than that for healthy tissues. Fricke and Morse have studied the electrical characteristics of malignant breast tumors. They observed higher permittivity values of tumor tissues at 20 KHz in comparison with normal tissues [4]. Roberts et al. found out an increment of the loss factor and the dielectric constant of normal breast tissue and fatty mammary tissues fibrosed by x-rays [5]. Same observation has been reported by Singh et al [6]. In 1988 Surowiec and colleagues carried out in vitro tests to find out the differences of characteristics between samples of breast cancer, samples of cancer and normal tissue combined with the boundary of the lesion, and samples of normal tissue only on frequency range between 20 kHz to 100 MHz. They found out that the conductivity and the dielectric constants of tissues of carcinoma are different across the sample groups [7]. Keywords: Permittivity, Dielectric Properties, Microwave Frequency, Tumor, Biomarker, Stages of Breast Cancer I. In this paper, a new method is employed to investigate whether there is a significant difference across three groups of breast cancer stages (stage 1, stage 2 and stage 3). This by measuring permittivity value of their urine samples as a function of microwave frequency. Existence of significant difference within different stages of breast cancer indicates the effect of cancer tumor progress on urine properties and possibility of using urine for breast cancer diagnostic purposes. Changes in the dielectric properties of urine reflect the progress of malignant tumor. INTRODUCTION A malignant tumor is a mass of cells that grow abnormally and invade surrounding tissues or invade different regions of the body. Malignant tumor which metastasizes from the breast cells is called breast cancer. Breast cancer is considered as the most common type of cancer in women (excluding skin cancers) [1-2]. Staging and Early detection of breast cancer is a key factor in prognosis, and consequently plays a major role in reducing mortality [3]. Staging of breast cancer is currently performed by information that is attained from the pathology report which is based upon detections by imaging exams, such as chest x-ray, abdominal ultrasound and computed tomography (CT or CAT scan, and bone scans). 20% failure of X-ray mammography to detect malignant tumors and limitations of other current methods such as ultrasound and MRI motivate scientist to seek for complimentary techniques to overcome these limitations. II. METHODS In this study, urine samples were collected from 19 breast cancer patients (stage 1: 6, stage 2: 7, stage 3: 6, women, age: 53.52 years old). Malaysians, Chinese and Indians, all from Malaysia were recruited in this study. The study was approved by university of Malaya medical center. Informed consent was obtained from all of the participants. Table 1 includes 1 ,((( QG,QWHUQDWLRQDO&RQIHUHQFHRQ(OHFWURQLF'HVLJQ,&('$XJXVW3HQDQJ0DOD\VLD In order to expect the relation between the stages before performing the statistical analysis, graphs of the permittivity of the subjects with different stages were plotted in both real part and imaginary part, Figures (1-2). Due to the overlapping of the graphs two subjects from each stage were chosen to depict the trend of the graphs. Data, obtained from the network vector analyzer, is analyzed statistically over frequency range from 4.1E+8 to 2E+10 Hz through the use of statistical analysis software, SPSS. Statistical analysis method applied by SPSS is One Way ANOVA test followed by Turkey test (Post Hoc Analysis). Statistical significance was set at P < 0.05. Significant differences in the real part, imaginary part and loss tangent of urine across the groups were analyzed and plotted. patients’ profiles. These samples were collected from patients prior to surgery, they are still carrying the lumps and have recently diagnosed as breast cancer patients (they have not taken medicine and received chemotherapy). Table 1 Profiles of patients participated in the study Stage Histo Type Chinese Tumour Size (cm) 11 3B 51 48 49 56 67 70 Malay Chinese Chinese Malay Indian Chinese 1.2 1.5 3 2 3.5 1.4 1 1 2A 1 2A 1(DCIS) 8 9 10 52 77 68 Indian Chinese Chinese 1 2 2 2A 2A 3B 11 41 Chinese 0.7 1 12 13 14 15 16 17 18 19 36 53 53 71 53 51 46 43 Chinese Chinese Chinese Chinese Chinese Chinese Chinese Chinese 3.2 6 5.5 3 3.1 1.4 5 6 2A 3A 2B 3C 2A 1 3B 3A IDC (Invasive Ductile Carcinoma) IDC IDC IDC IDC IDC DCIS (ductal carcinoma in situ) IDC IDC ILC (Invasive Lobular Carcinoma) DCIS with microinvasion IDC IDC IDC IDC IDC IDC ILC IDC No Age (Year Old) Ethnic Group 1 32 2 3 4 5 6 7 Urine Samples were taken after the subjects were refrained from having food, exercising and even brushing teeth at least 30 minutes before performing the test. Complex permittivity of the collected urine samples were measured using Network Vector Analyzer model (Agilent Technology, Agilent E8362C PNA network analyzer) using slim form probe with 2.4 mm male connector. The probe features a slim design. The slim design allows it to be used with smaller sample sizes. The slim form probe was connected to a sealed slim form holder that adapts 2.2 mm outer diameter to 10 mm inner diameter bracket as well as a midi sized adapters and bushings. Measurements were made by simply immersing the slim form probe in the samples. Calibration was conducted before each measurement. Calibration includes setting frequency between 10MHz to 20GHz, and configuring calibration using slim form probe and temperature of 25 ÛC. Two electrical properties of urine were measured, real part of permittivity (İƍ) which is called dielectric constant and imaginary part of permittivity (İƎ) which is called loss factor. Imaginary part and real part values were transferred and arranged in Excel. Based on the obtained real and imaginary parts’ values, loss tangent values were calculated according to the equation: Fig. 1 Real part of permittivity as a function of frequency. A. Real part of stage 1. B. Real part of stage 2. C. Real part of stage 3. III. RESULTS AND DISCUSSIONS 2 QG,QWHUQDWLRQDO&RQIHUHQFHRQ(OHFWURQLF'HVLJQ,&('$XJXVW3HQDQJ0DOD\VLD was found over a frequency range between 6.6 GHz to 17.8 GHz. Figures (3-5) represent the dielectric parameters as a function of frequency for urine samples. Dielectric parameters with the highest F number (the ratio of the difference between the groups to the difference within the same group) were compared between the groups of subjects. Moreover, the output of the statistical analysis of urine’s permittivity values reveals the existence of significant difference across the groups for each type of permittivity parameters. As shown in figures (3-5) the shape of the graphs for the mean of dielectric properties of stage1, stage2 and stage3 subjects follow almost the same trend. The dielectric properties of all stages in dielectric property decreases with increasing frequency while in loss factor and loss tangent the dielectric property of all stages increases with increasing frequency. However another common trend observed that stage1 appears to have the leading value for all dielectric parameters, while stage 2 has the least values for all dielectric parameters over the considered microwave frequency range. Meanwhile, the appearance of stage1 and stage2 has a seemingly overlapping presentation for dielectric constant parameter at frequencies greater than 18.6 GHz. It is obvious in all the graphs that the curves for the mean of all the groups are far from each other which indicates that a significance difference can be found between the groups in the dielectric parameters of urine. Moreover, in all the figures it can be seen that the graphs of stage 3 is between the graphs of stage 1 and stage 2 which is also agree with what was found by Qiao G. et al. for the conductivity values. He observed that the conductivity values of late stage breast cells is between the conductivity values of early stage and invasive cancer cells [13]. Fig.2 mean of dielectric constant parameter of urine for different stage of breast carcinoma IV. CONCLUSION According to the results obtained from the statistical analysis output, which are represented graphically and summarized in tables, it can be concluded that permittivity of urine of subjects with breast cancer has a potential in differentiating between different stages of breast cancer. The significant difference derived from the output of urine samples for all dielectric parameters (dielectric constant, loss factor and loss tangent) of permittivity can be considered as a starting point for more investigation in the staging research using microwave technique. The significant difference between the groups is appreciable because F numbers are quite high with the highest being 20.233 obtained at frequency of 18.4008 GHz for the loss factor parameter with a significant level of p =.000 and the least is F = 6.418 obtained at frequency of 13.003 GHz for the loss tangent parameter with significant level of p =.009. From table 2 it can be concluded that differentiation can be made between stage1-stage2 groups and stage2-stage3 groups from urine sample analysis considering dielectric constant parameter as a function of microwave frequency. While in loss factor parameter the significant level is divided into two parts according to the groups which a significant difference was found between them. The first part includes the groups: stage1-stage2 and stage2-stage3, the difference was significant mainly in the frequency range between 8.8-10.8 GHz. Differentiation between stage1-stage3 can also be made from urine sample analysis considering loss factor parameter as a function of microwave frequency range. The significant difference was obtained over a frequency range between 4.6 GHz to 6.8 GHz which is low relatively compared to the frequency range where the significant difference between stage2-stage3 and stage1-stage2 was obtained. In loss tangent parameter significant difference between stage1 and stage2 ACKNOWLEDGMENT The authors wish to extend his sincere appreciation to Universiti Malaysia Perlis (UniMAP) for giving the opportunities to use the research facilities in the Bio-chip Fabrication and characterization Lab and Ministry of Science, Technology & Innovation (MOSTI) for providing us with grant to carry out this research. The appreciation also goes to all the team members in the Institute of Nanoelectronic Engineering especially in the Nano Biochip Research Group. [2] Gibbins, D., et al., A comparison of a wide-slot and a stacked patch antenna for the purpose of breast cancer detection. IEEE transactions on antennas and propagation, 2010. 58(3): p. 665-673. [3] Nandi, J.R., et al., Scutt D Classification of breast masses in mammograms using genetic programmingand feature REFERENCES selection. . Med Bio Eng Comput, 2006. 44: p. 683-694. [4] Fricke, H. and S. 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