Three-dimensional quantitative ultrasound spectroscopic imaging of prostate was investigated clinically for the noninvasive detection and extent characterization of disease in cancer patients and compared to whole-mount, whole-gland histopathology of radical prostatectomy specimens. Fifteen patients with prostate cancer underwent a volumetric transrectal ultrasound scan before radical prostatectomy. Conventional-frequency (~ 5 MHz) ultrasound images and radiofrequency data were collected from patients. Normalized power spectra were used as the basis of quantitative ultrasound spectroscopy. Specifically, color-coded parametric maps of 0-MHz intercept, midband fit, and spectral slope were computed and used to characterize prostate tissue in ultrasound images. Areas of cancer were identified in whole-mount histopathology specimens, and disease extent was correlated to that estimated from quantitative ultrasound parametric images. Midband fit and 0-MHz intercept parameters were found to be best associated with the presence of disease as located on histopathology whole-mount sections. Obtained results indicated a correlation between disease extent estimated noninvasively based on midband fit parametric images and that identified histopathologically on prostatectomy specimens, with an r2 value of 0.71 (P < .0001). The 0-MHz intercept parameter demonstrated a lower level of correlation with histopathology. Spectral slope parametric maps offered no discrimination of disease. Multiple regression analysis produced a hybrid disease characterization model (r2 = 0.764, P < .05), implying that the midband fit biomarker had the greatest correlation with the histopathologic extent of disease. This work demonstrates that quantitative ultrasound spectroscopic imaging can be used for detecting prostate cancer and characterizing disease extent noninvasively, with corresponding gross three-dimensional histopathologic correlation.

A clinical study was undertaken investigating the efficacy of ultrasound to quantify cell death in tumor responses with cancer treatment. Patients (n = 25) with locally advanced breast cancer received anthracyline and taxane-based chemotherapy treatments over four to six months. The majority of patients went on to have a modified radical mastectomy and correlative whole mount histopathology. Data collection was carried out using an Ultrasonix-RP and an L15-5 6 cm transducer pulsed at 10 MHz with RF data collected five times during neoadjuvant chemotherapy. Data indicated increases of approximately 9 dBr (+/−1.67) maximally in ultrasound backscatter in patients who clinically responded to treatment. Patients assessed as responding poorly demonstrated significantly lower increases (2.3 +/− 1.7 dBr). Increases in 0-MHz intercept followed similar trends while increases in spectral slope were observed locally from tumor regions demonstrating increases in tissue echogenicity. This study demonstrates the potential of ultrasound to quantify changes in tumors in response to cancer treatment administration in a clinical setting. The results indicate that such responses can be detected early during a course of chemotherapy and should permit ineffective treatments to be changed to more efficacious ones potentially leading to improved treatment outcomes.

Pre-clinical and clinical studies were undertaken investigating the efficacy of ultrasound to quantify cell death in tumor responses with cancer treatment. Animals bearing tumours (n=48), and patients (n=24) with locally advanced breast cancer received various therapies including for patients anthracyline and taxane-based chemotherapy treatments over four to six months. Tumour cell-death was assessed in specimens after treatment using histopathology. Pre-clinical ultrasound data collection was carried out at low-frequency and high-frequency. For human imaging, low-frequency ultrasound data were collected 5 times during neoadjuvant chemotherapy. Data indicated considerable increases in ultrasound backscatter in animal tumours after treatment. Similar findings were observed in patients who clinically responded to treatment. Patients assessed as responding poorly demonstrated significantly lower increases. Increases in 0-MHz intercept followed similar trends while increases in spectral slope were observed locally from tumor regions demonstrating increases in tissue echogenicity. This study demonstrates the potential of ultrasound to quantify changes in tumours in response to cancer treatment administration in a pre-clinical and clinical setting. The results indicate that such responses can be detected early during a course of chemotherapy in patients and should permit ineffective treatments to be changed to more efficacious ones potentially leading to improved treatment outcomes.

Purpose: Quantitative ultrasound techniques have been recently shown to be capable of detecting cell death through studies conducted on in vitro and in vivomodels. This study investigates for the first time the potential of early detection of tumor cell death in response to clinical cancer therapy administration in patients using quantitative ultrasound spectroscopic methods. Experimental Design: Patients (n 1⁄4 24) with locally advanced breast cancer received neoadjuvant chemotherapy treatments. Ultrasound data were collected before treatment onset and at 4 times during treatment (weeks 1, 4, and 8, and preoperatively). Quantitative ultrasound parameters were evaluated for clinically responsive and nonresponding patients. Results: Results indicated that quantitative ultrasound parameters showed significant changes for patients who responded to treatment, and no similar alteration was observed in treatment-refractory patients. Suchdifferences between clinically andpathologically determined responding andnonresponding patients were statistically significant (P < 0.05) after 4 weeks of chemotherapy. Responding patients showed changes in parameters related to cell deathwith, on average, an increase inmid-bandfit and0-MHz intercept of 9.1 1.2 dBr and 8.9 1.9 dBr, respectively, whereas spectral slope was invariant. Linear discriminant analysis revealed a sensitivity of 100% and a specificity of 83.3% for distinguishing nonresponding patients by the fourth week into a course of chemotherapy lasting several months. Conclusion: This study reports for the first time that quantitative ultrasound spectroscopic methods can be applied clinically to evaluate cancer treatment responses noninvasively. The results form a basis for monitoring chemotherapy effects and facilitating the personalization of cancer treatment. Clin Cancer Res; 19(8); 2163–74. 2013 AACR.

PURPOSE: Ultrasound elastography is a new imaging technique that can be used to assess tissue stiffness. The aim of this study was to investigate the potential of ultrasound elastography for monitoring treatment response of locally advanced breast cancer patients undergoing neoadjuvant therapy. METHODS: Fifteen women receiving neoadjuvant chemotherapy had the affected breast scanned before, 1, 4, and 8 weeks following therapy initiation, and then before surgery. Changes in elastographic parameters related to tissue biomechanical properties were then determined and compared to clinical and pathologic tumor response after mastectomy. RESULTS: Patients who responded to therapy demonstrated a significant decrease (P < .05) in strain ratios and strain differences 4 weeks after treatment initiation compared to non-responding patients. Mean strain ratio and mean strain difference for responders was 81 ± 3% and 1 ± 17% for static regions of interest (ROIs) and 81 ± 3% and 6 ± 18% for dynamic ROIs, respectively. In contrast, these parameters were 102±2%, 110±17%, 101±4%, and 109±30% for non-responding patients, respectively. Strain ratio using static ROIs was found to be the best predictor of treatment response, with 100% sensitivity and 100% specificity obtained 4 weeks after starting treatment. CONCLUSIONS: These results suggest that ultrasound elastography can be potentially used as an early predictor of tumor therapy response in breast cancer patients.

1.2 Pitfalls of point-of-care ultrasound in obstetrics, Joshua A. Copel, Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Haven, CT, joshua.copel@yale.edu (invited overview). In the recent past, there have been multiple attempts to develop point-of-care ultrasound technology for obstetrics. To date, none have seen great success. This talk will review some of the issues specific to this application, focusing on specific approaches that could work.

Background: Tumour vasculature is an important component of tumour growth and survival. Recent evidence indicates tumour vasculature also has an important role in tumour radiation response. In this study, we investigated ultrasound and microbubbles to enhance the effects of radiation. Methods: Human bladder cancer HT-1376 xenografts in severe combined immuno-deficient mice were used. Treatments consisted of no, low and high concentrations of microbubbles and radiation doses of 0, 2 and 8 Gy in short-term and longitudinal studies. Acute response was assessed 24 h after treatment and longitudinal studies monitored tumour response weekly up to 28 days using power Doppler ultrasound imaging for a total of 9 conditions ( n =90 animals). Results: Quantitative analysis of ultrasound data revealed reduced blood flow with ultrasound-microbubble treatments alone and further when combined with radiation. Tumours treated with microbubbles and radiation revealed enhanced cell death, vascular normalisation and areas of fibrosis. Longitudinal data demonstrated a reduced normalised vascular index and increased tumour cell death in both low and high microbubble concentrations with radiation. Conclusion: Our study demonstrated that ultrasound-mediated microbubble exposure can enhance radiation effects in tumours, and can lead to enhanced tumour cell death.