| Neoadjuvant Chemotherapy(NAC)for breast cancer has been widely used in clinic.Regular and accurate evaluation of the efficacy before operation is the key to determine the treatment plan and effective treatment.However,the existing technology is insufficient for early evaluation and monitoring of the efficacy of NAC.As a functional imaging technology,breast electrical impedance scanning(EIS)has the advantages of non-invasive,convenient,non-radiation,simple operation and so on.It is sensitive to the changes of tissue function and blood supply in breast cancer,which provides a new idea for the evaluation of the efficacy of NAC of breast cancer.The research group has carried out the study of breast EIS imaging technology,which is suitable for the evaluation of the efficacy of NAC of breast cancer(NAC-EIS).This paper is the basic research of the NAC-EIS research,and the research contents are as follows:(1)Study on electrical impedance measurement methods of breast cancer tissue after the neoadjuvant chemotherapy.Breast cancer tissue will gradually decrease under the action of NAC.In order to accurately obtain the electrical impedance data of small volume cancer tissue,this study comprehensively compared the advantages and disadvantages of various electrical impedance measurement methods,and finally the two-electrode method was chosen to build a platform for measuring electrical impedance characteristics of breast cancer tissue after NAC with Agilent 4294A impedance analyzer as the core.The measurement frequency range is 100Hz～100MHz.The platform consists of three parts:a measuring system,a cylindrical measuring box with adjustable capacity and a temperature control system,which can measure the electrical impedance of biological tissues with length in 5mm～10mm.Through the test of the accuracy and precision of the platform,the measurement error of the platform in the 100Hz～100MHz frequency range is less than 8.2%,and the precision is less than 5%,which meets the electrical impedance measurement requirements of small volume breast cancer tissue samples after NAC.(2)Study on the correlation between electrical impedance characteristics and microstructural changes of breast cancer under NAC therapeutic grade.In order to study the changes of electrical impedance characteristics and the relationship between impedance spectrum characteristics and microstructure changes of breast cancer tissue and peri-cancer tissue under NAC therapeutic grade,human breast cancer cell T47D was selected to establish a breast cancer-bearing nude mouse model.The fresh breast cancer tissue and peri-cancer tissue treated with chemotherapeutic drugs(cyclophosphamide,fluorouracil and doxorubicin)were used as experimental objects.Based on the electrical impedance measurement platform of cancer tissue established by(1),under the experimental conditions of strictly controlling the tissue sample in vitro time(within 5 minutes),ambient temperature(37℃)and relative humidity(90%),the electrical impedance data of breast cancer and peri-cancer tissues under NAC therapeutic grade were measured and obtained.After the measurement,the tissue samples were immediately fixed in 4%paraformaldehyde solution for HE staining and immunohistochemical analysis,and the microstructure indexes(cell morphology index and microvessel density)were obtained.The experimental results show that:Under the same NAC grade,the electrical conductivity of cancer tissue gradually increased and the relative permittivity decreased with frequency,and with the increase of NAC grade,the conductivity and relative permittivity of breast cancer tissue decreased gradually.The difference of electrical conductivity of cancer tissue under NAC grade was statistically significant under 10MHz(p<0.05),and the difference of relative permittivity was significant at 100Hz～200Hz,2.5kHz～50kHz and 10MHz～100MHz(p<0.05).Under different NAC grade,there were significant differences in conductivity and relative permittivity between cancer tissue and pericarcinomatous tissue(p<0.01).In addition,there were significant differences in the characteristic parameters(ρ0、fcα and Δρα)of electrical impedance of cancer tissues under NAC-Ⅰ grade,NAC-Ⅱ grade and NAC-Ⅲgrade(p<0.01).ImageJ software was used to extract the cell morphological indexes of cancer tissue HE section:nuclear number,nuclear area and nuclear/cytoplasmic ratio.The statistical analysis of the above indexes showed that there was a significant difference in the number of nuclei between NAC-Ⅰ grade and NAC-Ⅱ grade(p<0.001),and the immunohistochemical results showed that the difference of microvessel density in cancer tissue was statistically significant(p<0.05).Through regression analysis,the functional relationship between Cole-Cole model parameters(ρ0 and fcα)and its microstructure(cell morphology index,MVD)under NAC therapeutic grade was obtained.The results showed that under different efficacy grade of NAC,ρ0 and fcα were exponentially related to the number of nuclei and MVD count.The functional relationship between the parameters of Cole-Cole model of cancer tissue and its microstructure index was established,which provides a quantitative reference for using the parameters of electrical impedance characteristics of cancer tissue to evaluate the curative effect classification of NAC.(3)Exploratory research on NAC-EIS simulation data classification and feature selection based on support vector machine.On the basis of preliminary obtaining the change rule of electrical impedance characteristics of breast cancer tissue under NAC therapeutic grade,based on the breast EIS simulation model,this part exploratively carried out the research on breast EIS detection data classification and feature screening under NAC therapeutic grade.First of all,based on three-dimensional software(Mimics,Geomagic and CAD)and COMSOL software,a fine breast EIS simulation model was constructed based on MRI scanning sequence of breast,and the electrical impedance characteristic data(conductivity and relative permittivity)of breast cancer tissue and peri-cancer tissue under different efficacy grade of NAC obtained in(1)were imported into the simulation model to get the breast EIS simulation model of three-grade of NAC.Secondly,based on the COMSOL simulation data under different conditions,matlab software was used to extract image information parameters(semi-height area normalized of bright spot)and frequency domain information parameters(low-frequency conductivity G0,high-frequency conductivity G∞,characteristic frequency fc).Finally,the characteristic parameters or their combinations that can characterize the NAC efficacy grade were selected by the support vector machine(SVM)method,in order to provide methodological basis and data support for the classification of breast EIS test data under different efficacy grade of NAC.The simulation results show that:In the combination of characteristic parameters,the average classification accuracy of G∞ is very low(41.3%),and the average classification accuracy of the other three(fc、G0 and SAN)is higher(more than 80%),where the average classification accuracy of the combination of fc+G0+SAN is the highest(92.8%)..In addition,we drew the ROC curve of the combination of 15 characteristic parameters under the three categories of NAC,and calculated the mean value of AUC.The results showed that under the three categorie of NAC,the mean value of AUC of the feature combination of fc+G0+SAN and G∞+fc+G0+SAN was the highest(0.92).Based on a comprehensive comparison of the average classification accuracy under various feature parameter combinations and the mean value of AUC,we preliminarily suggest that the combination of fc+G0+SAN should be selected as the feature parameter combination to distinguish the breast EIS detection results under the third-grade efficacy of NAC.The characteristics and innovations of this paper are as follows:(1)The characteristics of electrical impedance spectrum of breast cancer tissue and peri-cancer tissue under NAC grade were obtained,and the Cole-Cole model parameters(ρ0 and fcα)and microstructure indexes(number of nuclei and microvessel density)of breast cancer tissue under NAC grade were extracted,and the corresponding relationship between them was fitted.It not only reveals the close relationship between the electrical impedance characteristics of cancer tissue and the grade of NAC treatment from the point of view of histology and cytology,but also provides impedance data support for the application of bioelectrical impedance imaging in breast cancer NAC efficacy evaluation.(2)Based on the breast EIS simulation model,the classification of breast EIS detection data and the selection of characteristic parameters under different efficacy grade of NAC are studied exploringly,which provides the methodological basis and data support for the application of breast EIS imaging technology in clinical NAC efficacy evaluation. |
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