Monitoring Breast Cancer Response to Neoadjuvant Chemotherapy Using Probability Maps Derived from Quantitative Ultrasound Parametric Images.

OBJECTIVE: Neoadjuvant chemotherapy (NAC) is widely used in the treatment of breast cancer. However, to date, there are no fully reliable, non-invasive methods for monitoring NAC. In this article, we propose a new method for classifying NAC-responsive and unresponsive tumors using quantitative ultrasound. METHODS: The study used ultrasound data collected from breast tumors treated with NAC. The proposed method is based on the hypothesis that areas that characterize the effect of therapy particularly well can be found. For this purpose, parametric images of texture features calculated from tumor images were converted into NAC response probability maps, and areas with a probability above 0.5 were used for classification. RESULTS: The results obtained after the third cycle of NAC show that the classification of tumors using the traditional method (area under the ROC curve AUC = 0.81 - 0.88) can be significantly improved thanks to the proposed new approach (AUC = 0.84-0.94). This improvement is achieved over a wide range of cutoff values (0.2-0.7), and the probability maps obtained from different quantitative parameters correlate well. CONCLUSION: The results suggest that there are tumor areas that are particularly well suited to assessing response to NAC. SIGNIFICANCE: The proposed approach to monitoring the effects of NAC not only leads to a better classification of responses, but also may contribute to a better understanding of the microstructure of neoplastic tumors observed in an ultrasound examination.

Assessment of breast cancer response to neoadjuvant chemotherapy based on ultrasound backscattering envelope statistics.

PURPOSE: Neo-adjuvant chemotherapy (NAC) is used in breast cancer before tumor surgery to reduce the size of the tumor and the risk of spreading. Monitoring the effects of NAC is important because in a number of cases the response to therapy is poor and requires a change in treatment. A new method that uses quantitative ultrasound to assess tumor response to NAC has been presented. The aim was to detect NAC unresponsive tumors at an early stage of treatment. METHODS: The method assumes that ultrasound scattering is different for responsive and nonresponsive tumors. The assessment of the NAC effects was based on the differences between the histograms of the ultrasound echo amplitude recorded from the tumor after each NAC dose and from the tissue phantom, estimated using the Kolmogorov-Smirnov statistics (KSS) and the symmetrical Kullback-Leibler divergence (KLD). After therapy, tumors were resected and histopathologically evaluated. The percentage of residual malignant cells was determined and was the basis for assessing the tumor response. The data set included ultrasound data obtained from 37 tumors. The performance of the methods was assessed by means of the area under the receiver operating characteristic curve (AUC). RESULTS: For responding tumors, a decrease in the mean KLD and KSS values was observed after subsequent doses of NAC. In nonresponding tumors, the KLD was higher and did not change in subsequent NAC courses. Classification based on the KSS or KLD parameters allowed to detect tumors not responding to NAC after the first dose of the drug, with AUC equal 0.83 ± $\pm$ 0.06 and 0.84 ± $\pm$ 0.07, respectively. After the third dose, the AUC increased to 0.90 ± $\pm$ 0.05 and 0.91 ± $\pm$ 0.04, respectively. CONCLUSIONS: The results indicate the potential usefulness of the proposed parameters in assessing the effectiveness of the NAC and early detection of nonresponding cases.

Quantitative Assessment of the Echogenicity of a Breast Tumor Predicts the Response to Neoadjuvant Chemotherapy.

The aim of the study was to improve monitoring the treatment response in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). The IRB approved this prospective study. Ultrasound examinations were performed prior to treatment and 7 days after four consecutive NAC cycles. Residual malignant cell (RMC) measurement at surgery was the standard of reference. Alteration in B-mode ultrasound (tumor echogenicity and volume) and the Kullback-Leibler divergence (kld), as a quantitative measure of amplitude difference, were used. Correlations of these parameters with RMC were assessed and Receiver Operating Characteristic curve (ROC) analysis was performed. Thirty-nine patients (mean age 57 y.) with 50 tumors were included. There was a significant correlation between RMC and changes in quantitative parameters (KLD) after the second, third and fourth course of NAC, and alteration in echogenicity after the third and fourth course. Multivariate analysis of the echogenicity and KLD after the third NAC course revealed a sensitivity of 91%, specificity of 92%, PPV = 77%, NPV = 97%, accuracy = 91%, and AUC of 0.92 for non-responding tumors (RMC ≥ 70%). In conclusion, monitoring the echogenicity and KLD parameters made it possible to accurately predict the treatment response from the second course of NAC.

Aortic root movement correlation with the function of the left ventricle.

Echocardiographic assessment of systolic and diastolic function of the heart is often limited by image quality. However, the aortic root is well visualized in most patients. We hypothesize that the aortic root motion may correlate with the systolic and diastolic function of the left ventricle of the heart. Data obtained from 101 healthy volunteers (mean age 46.6 ± 12.4) was used in the study. The data contained sequences of standard two-dimensional (2D) echocardiographic B-mode (brightness mode, classical ultrasound grayscale presentation) images corresponding to single cardiac cycles. They also included sets of standard echocardiographic Doppler parameters of the left ventricular systolic and diastolic function. For each B-mode image sequence, the aortic root was tracked with use of a correlation tracking algorithm and systolic and diastolic values of traveled distances and velocities were determined. The aortic root motion parameters were correlated with the standard Doppler parameters used for the assessment of LV function. The aortic root diastolic distance (ARDD) mean value was 1.66 ± 0.26 cm and showed significant, moderate correlation (r up to 0.59, p < 0.0001) with selected left ventricular diastolic Doppler parameters. The aortic root maximal diastolic velocity (ARDV) was 10.8 ± 2.4 cm/s and also correlated (r up to 0.51, p < 0.0001) with some left ventricular diastolic Doppler parameters. The aortic root systolic distance (ARSD) was 1.63 ± 0.19 cm and showed no significant moderate correlation (all r values < 0.40). The aortic root maximal systolic velocity (ARSV) was 9.2 ± 1.6 cm/s and correlated in moderate range only with peak systolic velocity of medial mitral annulus (r = 0.44, p < 0.0001). Based on these results, we conclude, that in healthy subjects, aortic root motion parameters correlate significantly with established measurements of left ventricular function. Aortic root motion parameters can be especially useful in patients with low ultrasound image quality precluding usage of typical LV function parameters.

Monitoring the response to neoadjuvant chemotherapy in patients with breast cancer using ultrasound scattering coefficient: A preliminary report.

Objective: Neoadjuvant chemotherapy was initially used in locally advanced breast cancer, and currently it is recommended for patients with Stage 3 and with early-stage disease with human epidermal growth factor receptors positive or triple-negative breast cancer. Ultrasound imaging in combination with a quantitative ultrasound method is a novel diagnostic approach. Aim of study: The aim of this study was to analyze the variability of the integrated backscatter coefficient, and to evaluate their use to predict the effectiveness of treatment and compare to ultrasound examination results. Material and method: Ten patients (mean age 52.9) with 13 breast tumors (mean dimension 41 mm) were selected for neoadjuvant chemotherapy. Ultrasound was performed before the treatment and one week after each course of neoadjuvant chemotherapy. The dimensions were assessed adopting the RECIST criteria. Tissue responses were classified as pathological response into the following categories: not responded to the treatment (G1, cell reduction by ≤9%) and responded to the treatment partially: G2, G3, G4, cell reduction by 10-29% (G2), 30-90% (G3), >90% (G4), respectively, and completely. Results: In B-mode examination partial response was observed in 9/13 cases (completely, G1, G3, G4), and stable disease was demonstrated in 3/13 cases (completely, G1, G4). Complete response was found in 1/13 cases. As for backscatter coefficient, 10/13 tumors (completely, and G2, G3, and G4) were characterized by an increased mean value of 153%. Three tumors 3/13 (G1) displayed a decreased mean value of 31%. Conclusion: The variability of backscatter coefficient, could be associated with alterations in the structure of the tumor tissue during neoadjuvant chemotherapy. There were unequivocal differences between responded and non-responded patients. The backscatter coefficient analysis correlated better with the results of histopathological verification than with the B-mode RECIST criteria.Objective: Neoadjuvant chemotherapy was initially used in locally advanced breast cancer, and currently it is recommended for patients with Stage 3 and with early-stage disease with human epidermal growth factor receptors positive or triple-negative breast cancer. Ultrasound imaging in combination with a quantitative ultrasound method is a novel diagnostic approach. Aim of study: The aim of this study was to analyze the variability of the integrated backscatter coefficient, and to evaluate their use to predict the effectiveness of treatment and compare to ultrasound examination results. Material and method: Ten patients (mean age 52.9) with 13 breast tumors (mean dimension 41 mm) were selected for neoadjuvant chemotherapy. Ultrasound was performed before the treatment and one week after each course of neoadjuvant chemotherapy. The dimensions were assessed adopting the RECIST criteria. Tissue responses were classified as pathological response into the following categories: not responded to the treatment (G1, cell reduction by ≤9%) and responded to the treatment partially: G2, G3, G4, cell reduction by 10­29% (G2), 30­90% (G3), >90% (G4), respectively, and completely. Results: In B-mode examination partial response was observed in 9/13 cases (completely, G1, G3, G4), and stable disease was demonstrated in 3/13 cases (completely, G1, G4). Complete response was found in 1/13 cases. As for backscatter coefficient, 10/13 tumors (completely, and G2, G3, and G4) were characterized by an increased mean value of 153%. Three tumors 3/13 (G1) displayed a decreased mean value of 31%. Conclusion: The variability of backscatter coefficient, could be associated with alterations in the structure of the tumor tissue during neoadjuvant chemotherapy. There were unequivocal differences between responded and non-responded patients. The backscatter coefficient analysis correlated better with the results of histopathological verification than with the B-mode RECIST criteria.

Breast-lesions characterization using Quantitative Ultrasound features of peritumoral tissue.

The presented studies evaluate for the first time the efficiency of tumour classification based on the quantitative analysis of ultrasound data originating from the tissue surrounding the tumour. 116 patients took part in the study after qualifying for biopsy due to suspicious breast changes. The RF signals collected from the tumour and tumour-surroundings were processed to determine quantitative measures consisting of Nakagami distribution shape parameter, entropy, and texture parameters. The utility of parameters for the classification of benign and malignant lesions was assessed in relation to the results of histopathology. The best multi-parametric classifier reached an AUC of 0.92 and of 0.83 for outer and intra-tumour data, respectively. A classifier composed of two types of parameters, parameters based on signals scattered in the tumour and in the surrounding tissue, allowed the classification of breast changes with sensitivity of 93%, specificity of 88%, and AUC of 0.94. Among the 4095 multi-parameter classifiers tested, only in eight cases the result of classification based on data from the surrounding tumour tissue was worse than when using tumour data. The presented results indicate the high usefulness of QUS analysis of echoes from the tissue surrounding the tumour in the classification of breast lesions.

Monitoring breast cancer response to neoadjuvant chemotherapy with ultrasound signal statistics and integrated backscatter.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is used in patients with breast cancer to reduce tumor focus, metastatic risk, and patient mortality. Monitoring NAC effects is necessary to capture resistant patients and stop or change treatment. The existing methods for evaluating NAC results have some limitations. The aim of this study was to assess the tumor response at an early stage, after the first doses of the NAC, based on the variability of the backscattered ultrasound energy, and backscatter statistics. The backscatter statistics has not previously been used to monitor NAC effects. METHODS: The B-mode ultrasound images and raw radio frequency data from breast tumors were obtained using an ultrasound scanner before chemotherapy and 1 week after each NAC cycle. The study included twenty-four malignant breast cancers diagnosed in sixteen patients and qualified for neoadjuvant treatment before surgery. The shape parameter of the homodyned K distribution and integrated backscatter, along with the tumor size in the longest dimension, were determined based on ultrasound data and used as markers for NAC response. Cancer tumors were assigned to responding and non-responding groups, according to histopathological evaluation, which was a reference in assessing the utility of markers. Statistical analysis was performed to rate the ability of markers to predict the final NAC response based on data obtained after subsequent therapeutic doses. RESULTS: Statistically significant differences (p<0.05) between groups were obtained after 2, 3, 4, and 5 doses of NAC for quantitative ultrasound markers and after 5 doses for the assessment based on maximum tumor dimension. Statistical analysis showed that, after the second and third NAC courses the classification based on integrated backscatter marker was characterized by an AUC of 0.69 and 0.82, respectively. The introduction of the second quantitative marker describing the statistical properties of scattering increased the corresponding AUC values to 0.82 and 0.91. CONCLUSIONS: Quantitative ultrasound information can characterize the tumor's pathological response better and at an earlier stage of therapy than the assessment of the reduction of its dimensions. The introduction of statistical parameters of ultrasonic backscatter to monitor the effects of chemotherapy can increase the effectiveness of monitoring and contribute to a better personalization of NAC therapy.

Determining temperature distribution in tissue in the focal plane of the high (>100 W/cm(2)) intensity focused ultrasound beam using phase shift of ultrasound echoes.

In therapeutic applications of High Intensity Focused Ultrasound (HIFU) the guidance of the HIFU beam and especially its focal plane is of crucial importance. This guidance is needed to appropriately target the focal plane and hence the whole focal volume inside the tumor tissue prior to thermo-ablative treatment and beginning of tissue necrosis. This is currently done using Magnetic Resonance Imaging that is relatively expensive. In this study an ultrasound method, which calculates the variations of speed of sound in the locally heated tissue volume by analyzing the phase shifts of echo-signals received by an ultrasound scanner from this very volume is presented. To improve spatial resolution of B-mode imaging and minimize the uncertainty of temperature estimation the acoustic signals were transmitted and received by 8 MHz linear phased array employing Synthetic Transmit Aperture (STA) technique. Initially, the validity of the algorithm developed was verified experimentally in a tissue-mimicking phantom heated from 20.6 to 48.6 °C. Subsequently, the method was tested using a pork loin sample heated locally by a 2 MHz pulsed HIFU beam with focal intensity ISATA of 129 W/cm(2). The temperature calibration of 2D maps of changes in the sound velocity induced by heating was performed by comparison of the algorithm-determined changes in the sound velocity with the temperatures measured by thermocouples located in the heated tissue volume. The method developed enabled ultrasound temperature imaging of the heated tissue volume from the very inception of heating with the contrast-to-noise ratio of 3.5-12 dB in the temperature range 21-56 °C. Concurrently performed, conventional B-mode imaging revealed CNR close to zero dB until the temperature reached 50 °C causing necrosis. The data presented suggest that the proposed method could offer an alternative to MRI-guided temperature imaging for prediction of the location and extent of the thermal lesion prior to applying the final HIFU treatment.